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Maeda and Khatami Clin Trans Med (2018) 7:11
https://doi.org/10.1186/s40169-018-0185-6
PERSPECTIVE
Analyses of repeated failures in cancer
therapy for solid tumors: poor tumor-selective
drug delivery, low therapeutic efficacy
and unsustainable costs
Hiroshi Maeda1,2,3*† and Mahin Khatami4*†
Abstract
For over six decades reductionist approaches to cancer chemotherapies including recent immunotherapy for solid
tumors produced outcome failure-rates of 90% (±5) according to governmental agencies and industry. Despite tre-
mendous public and private funding and initial enthusiasm about missile-therapy for site-specific cancers, molecular
targeting drugs for specific enzymes such as kinases or inhibitors of growth factor receptors, the outcomes are very
bleak and disappointing. Major scientific reasons for repeated failures of such therapeutic approaches are attributed
to reductionist approaches to research and infinite numbers of genetic mutations in chaotic molecular environment
of solid tumors that are bases of drug development. Safety and efficacy of candidate drugs tested in test tubes or
experimental tumor models of rats or mice are usually evaluated and approved by FDA. Cost-benefit ratios of such
‘targeted’ therapies are also far from ideal as compared with antibiotics half a century ago. Such alarming records
of failure of clinical outcomes, the increased publicity for specific vaccines (e.g., HPV or flu) targeting young and old
populations, along with increasing rise of cancer incidence and death created huge and unsustainable cost to the
public around the globe. This article discusses a closer scientific assessment of current cancer therapeutics and vac-
cines. We also present future logical approaches to cancer research and therapy and vaccines.
Keywords: Cancer vaccines, Cancer financial toxicity, Cancer therapeutic failure, Cancer/medical establishment,
Decision makers, Enhanced permeability and retention (EPR), Genomic mutations, Immunotherapy, Incredible price
of drugs, Inflammation, Medical/scientific ponzi schemes, Molecular target drugs, Molecular false flags, Nanoparticles,
Oxidative stress and mutations, Precision and personalized medicine, ROS, Targeted therapy, Tarnished immune
surveillance, Yin and Yang of acute inflammation
© The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License
(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium,
provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made.
Background
Review of over six decades of cancer chemotherapy and
tremendous investment for understanding cancer biology
and cure reveal minimal or partial success for only the
treatment of leukemia and non-solid or soft tissue tumors
[1–7].1,2 e latest statistics in cancer incidence, mortal-
ity and cancer burden are growing at an alarming pace
around the globe, according to governmental agencies
and private organizations including the International
Agency for Research on Cancer (IARC, an agency within
1 In February of 2012, in a National Cancer Institute (NCI) Board meet-
ing report on cancer therapy admitted that success rate being 15% also, in
March of 2012, in a Metabolon conference in Bethesda, Maryland, company
professionals reported that 95% of cancer drug developed failed.
2 Medscape December 5, 2011 (Washington DC) reported by Dr. Foji
(NCI) ’zero (is) the number of targeted therapies that prolonged survival by
1year’ when compared with conventional treatment.
Open Access
*Correspondence: maedabdr@sweet.ocn.ne.jp; mkgoodness@aol.com
†Hiroshi Maeda and Mahin Khatami contributed equally to this work
1 BioDynamics Research Foundation, Kumamoto University (Med),
Kumamoto, Kenshin Bldg 3F, Kuwamizu 1-chome, 24-6, Chuo-ku,
Kumamoto 862-0954, Japan
4 Inflammation, Aging and Cancer, National Cancer Institute, The National
Institutes of Health, Bethesda, MD, USA
Full list of author information is available at the end of the article
Page 2 of 20
Maeda and Khatami Clin Trans Med (2018) 7:11
World Health Organization (WHO), or the American
Cancer Society (ACS), [8–12].3 In 2014, IARC reported
that the global war against cancer cannot be won by
treatment alone, and recommended the need for urgent
implementation of efficient prevention strategies to pre-
vent cancer crisis [8]. Clinical trials using specific cancer
drugs repeatedly failed patients and the expensive thera-
pies discontinued after loss of patients [13–16].
Other recently published articles on basic research and
clinical studies of cancer and pathogen-specific vaccines
have raised serious concerns about the worthiness, hid-
den agenda and high costs of these reductionist
approaches to such projects that are toxic and repeatedly
failed the public [14–40]. e majority of cancer claimed
‘targeted’ therapies, ‘personalized’ or ‘precision’ medicine
are based on identification of evolving mutation-derived
molecules and use of specific and expensive technologies
with little or no benefit to patients. e safety and politi-
cal agenda behind heavy publicity for targeting the public
to consume a wide range of specific vaccines against a
numbers of viruses (e.g., HPV, measles, meningitis,
Ebola, Flu, Zika) are topics of debates and controversies
for effectiveness of such undertaking (details below) [18,
22, 39–45].4,5,6
In majority of claimed cancer ‘targeted’ therapies,
‘personalized’ or ‘precision’ medicine or the recently
fashionable immunotherapeutic approaches, drugs are
developed as inhibitors of one or combination of spe-
cific over‐, or under‐expression of cancer-associated
molecules such as various proteins, epitopes, growth
factors, cytokines/chemokines, receptor/adaptor mol-
ecules or enzymes (e.g., Kras, BCR, PI3K, CD11, CD22,
Myc, BRCA2, ALK, IL-10, IL-12, p53, p27, p70, MAPKs,
TKIs, VEGF, EGF), identified in the molecular tsunami of
site-specific cancers [18–22, 27–39, 43–45, 65, 66]. e
molecular targets are derived from mutated genetic com-
ponents (e.g., DNA damage, hypo-, hyper-methylated
epigenetic modifications and expression products). While
the isolated molecular entities are parts of the highly
3 June 1, 2012, E Berger (CNBC program) in an interview with then presi-
dent of MD Anderson, DePinho confirmed that 95% of cancer drugs for
solid tumors fail –http://blog.chron.com/sciguy/2012/06/m-d-anderson-
president-goes-on-cnbc-extols-his-own-company.
4 “Is e U.S. Becoming a Police State to Force Mandatory Vaccination?”;
also “American Academy of Pediatrics wants a Police-State approach to vac-
cination”, Health Impact News, September 14, 2016.
5 “Complaint to the European ombudsman over maladministration at the
European Medicines Agency (EMA) in relation to the safety of the HPV
vaccines”. Letter signed by professionals regarding HPV safety concerns;
Nordic Cochrane Centre, Copenhagen, Denmark. October 10, 2016.
6 Robert F. Kennedy, Jr. Exposes New Evidence of CDC Corruption Regard-
ing Vaccines and Autism and related reports on vaccines safety concerns-
World of Mercury-accessed from Health Impact News, September 18, 2017.
heterogeneous and chaotic landscape in cancer biology,
they should not be considered as ‘target’ for therapy as
they have little/no value on their own for translational
purposes although they may work in mouse models for
the selected conditions and duration of therapy which do
not apply to human (see below) [18, 22, 38, 39, 44–46].
Patients with stage III or IV diseases who are treated
in clinics, often advance to metastatic stages and develop
drug resistance and relapse involving lymph nodes, liver,
lungs, bones, and brain resulting in systemic multiple
organ failures (MOFs) and damages to vasculature and
induction or activation of proteolytic cascade resulting
in disseminated intravascular coagulation (DIC) which
are most difficult to cure as many physicians experienced
[35, 39, 44, 46–49].
In this perspective, attempts were made to briefly
review the various therapeutic modalities that have been
used for treatment of solid tumors, immunotherapy or
safety of pathogen-specific vaccines and the associated
cancer financial toxicities for the past several decades
[14–18, 22, 29–31, 39–87] (see footnote 3–8).
Scientific bases for repeatedly failed therapeutic
approaches. Molecular false flags and distorted
foundations for chemo‑immunotherapy
Scientific analyses of data on the repeated failures of
the majority of highly publicized and well-funded can-
cer projects that are claimed as ‘targeted’ therapies,
‘personalized’ or ‘precision’ medicine or the recent tri-
als on ‘immunotherapies’ are rarely reported. e deci-
sion makers of such expensive, out-of-focus and fuzzy
undertakings seldom consider the life-threatening con-
sequences of wrong and reductionist approaches to drug
development for patients and the tremendous economic
burden to the society. e irresponsible decision makers
of such undertakings, either abandon data on failed out-
comes or downplay and ignore the serious consequences
of drugs that, at best, postpone patient’s death-sentence
for a few months of remission [18–22, 33–39, 44–47].
Once such expensively developed drugs (poisons) failed
patients the trials are suspended and soon drug manu-
factures and decision makers proceed to make minor
or major changes to the same protocols (e.g., changes
in dosage, route and frequency of drug administration
or use of combination drugs). Such strategies are again
highly publicized as “new” approaches to cancer drugs
through control of media using the same empty prom-
ises to justify additional support for recruiting desperate
patients in expensive schemes of clinical trials [2–5, 7,
13, 18, 22, 30–38, 41–44].
To better appreciate the issues, according to the
NCI updated report (National Cancer Institute Budget
Page 3 of 20
Maeda and Khatami Clin Trans Med (2018) 7:11
Proposal for 2010), the list of major cancer funded stud-
ies included the following [reviewed in 44].
i. 12 new drugs or drugs uses (protocol) were approved
by FDA;
ii. 348 phase III oncology trials are ongoing;
iii. 861 cancer drugs are in some form of trial process;
iv. 2000-plus clinical trials are accepting children and
young adults;
v. 200-plus prevention trials are ongoing and 100-plus
screening trials are open.
Since 2010, the above list has grown to include several
immunotherapies and numerous pathogen-specific vac-
cines and cancer trials for recruiting children to clinical
trials using the same reductionist and chaotic approaches
for young patients (Khatami, manuscript in preparation).
Major scientific reasons for repeated failed therapeutic
approaches are outlined below:
a. Review of data on molecular targeted therapies shows
that the principal scientific reasons for repeated fail-
ures are identification of endless genetic mutations in
the chaotic molecular environment of cancer [2–4,
17–19, 21, 22, 25–31, 37–40, 44, 45, 65]. Such mov-
ing targets on identification of specific and evolving
mutations that are bases of the drugs (e.g., potent
apoptotic factors or monoclonal antibodies against
specific enzymes) that patients are treated with, are
highly toxic and cause severe immunobiological and
systemic damages to the normal functioning of tis-
sues/organs, rather than being curative for patients.
e life-threatening side effects of claimed ‘molecu-
lar targeted’ therapies, ‘personalize’ or ‘precision’
medicine include drug-resistance and cancer relapse,
anorexia, cachexia, sarcopenia, leukopenia, thrombo-
embolism and metastasis leading to multiple local or
distant organ failures (MOFs) and death [19, 22, 28,
37–39, 44, 45]. erefore, at advanced stages of the
disease, the current therapeutic modalities are quite
limited in their effectiveness. In addition, the severe
and life-threatening side effects of drugs and loss of
quality of life (QOL) would cancel out any short-lived
benefits from temporary remission of cancer.
b. For several decades, numerous circumstantial data,
retrospective epidemiological or clinical reports dem-
onstrated that chronic infections, persistent injuries
or inflammation induce precancerous state of tissue
that increases the risk of many cancers, particularly
in aging individuals [37–39, 44, 45]. For example, the
pioneering work by Maeda’s group [46–61] demon-
strated that infection with influenza virus triggered
activation of ROS-generating cascade [e.g., O2
·− gener-
ation via activation of xanthine oxides, in parallel with
activation of iNOS (generation of NO), and formation
of peroxynitrite (ONOO−)] in experimental models
of influenza, that causes viral genes mutations and
other immune and non-immune modifications. Drug
resistance and induction of mutations in chronic
infection of hepatitis virus, or H. pylori, or Salmonella
typhimurium infection were also suggestive of the
impact of ROS/RNS formation, affecting the genomic
structure [46–61]. Numerous other reports also dem-
onstrated a role of immune/inflammatory responses
in site-specific tissues leading to initiation and pro-
gression of nearly all chronic illnesses including can-
cer, as well as neurodegenerative and autoimmune
diseases [18, 22, 37–39, 44, 45, 51–54, 62–66]. ese
data support the notion that persistent inflammatory
conditions offer powerful chemical, biological and
environmental hazards in causing additional genetic
alterations at site-specific tissues. Consequently, het-
erogeneity of such molecular targets and epitopic
antigenicity, and distorted molecular components in
cancers could render antidote-strategy ineffective and
insufficient [18, 22, 36–39, 44, 45, 62–66].
c. Recent attempts on extensive trials of cancer vaccines,
using viral structures or substructures against several
cancers such as cervices, prostate, lung, pancreatic
and skin also failed to produce the overall protective
clinical outcomes [39–45, 76–78].7 While the prophy-
lactic vaccinations could be the most effective and
rational medical preventive strategies, their systemic
immunity and effectiveness against cancer is debata-
ble. e recent heavily publicized vaccines against
human papillomavirus (HPV) such as Gardasil™, or
Cervarix™ for prevention of cervical cancers or men-
ingitis vaccines that target young generation, particu-
larly in the United States raise concerns for safety and
efficacy of such vaccines [39, 44, 45]. e short or
long-term health hazards, efficacy and safety of path-
ogen-specific vaccines such as virus-contaminated
polio vaccines, pneumonia, meningitis, HPV or Swine
flu vaccines in the induction of vaccine-(antigen-load)
related allergies, autoimmune or neurodegenerative
diseases have been raised in a number of reports [39–
45, 76–78]. Concerned parents often have to make
religion and faith to resist or protest forced vaccina-
tion of their school-aged children (Khatami personal
communication). e elaborate epitopic targets of
cancer seem to have limited prospects and therapeu-
tic cancer vaccination is an area of questionable effi-
cacy for immunotherapy and safety [39–45].
7 Lisa Stark, Legal Correspondence, on Vaccines—PBS News Hour Septem-
ber 26, 2017.
Page 4 of 20
Maeda and Khatami Clin Trans Med (2018) 7:11
d. As recently reported, a closer look at cancer science
reveals that highly powered structure (hierarchy) in
cancer/medical establishment (system) versus anti-
system and chaotic approaches to cancer research and
therapy (‘medical/scientific ponzi schemes’) are potent
recipes for failed therapeutics that kills patients but
generates huge corporate profit [39, 44, 45].
e. e recent reports on immunotherapy offer more
logical approaches for treating certain tumors (e.g.,
melanoma, urogenital, breast, non-small cell lung-
NSCLC) as they are immunogenic in nature, com-
pared with the identification of endless mutation
derived ‘targeted’ therapies that repeatedly failed in
patients [22, 36, 46, 62–65, 79–87]. However, carry-
ing out such reductionist studies under the different
name of immunotherapy present the same narrow
views of cancer biology and are far from being effec-
tive for cancer patients. In these studies, little consid-
erations are given to the cellular immune composi-
tion of site-specific tissues, the immune-non-immune
local or systemic compensatory response mecha-
nisms, the bioenergetics and oxido redox profiles of
tissues toward checkpoint inhibition, as well as, the
host immune and non-immune interactions with
recruited cells and the adverse responses that are
observed following therapy [12, 22, 36, 39, 64, 65, 82].
Effective cancer immunotherapy requires systematic
understanding of the mechanisms that contribute
to the ability of tumor cells to escape and bypass the
immune surveillance by induction of decoy receptors,
enhanced immune tolerance and loss of mitochon-
drial function (mitophagy), altered anabolic (growth-
promoting) and catabolic (necrosis or growth-arrest-
ing) recycling proteins/lipids pathways (autophagy)
in tissues. ese interdependent complex pathways
were defined to be provided through the two biologi-
cally opposing arms of Yin (tumoricidal, apoptosis,
growth arrest) and Yang (tumorigenic, wound healing
or growth promote) pathways of acute inflammation
or effective immunity [18, 22, 37–39, 44, 45, 62–65].
f. Except for the results of a series of accidental discov-
eries that were established in 1980s by Khatami and
collaborators [22, 65, 88–92] there is little or no study
to identify the early events in the loss of effective
immunity that would progressively lead to tumorigen-
esis and angiogenesis. Analyses of the original data
on experimental models of acute and chronic ocu-
lar inflammatory diseases are suggestive of the only
direct evidence on inflammation-induced time course
kinetics of developmental phases of immune dysfunc-
tion toward tumorigenesis and angiogenesis. In 2014,
Khatami further demonstrated the only evidence on
interactions and synergies between host and recruited
immune and non-immune cells toward tumorigenesis
and angiogenesis [37]. It was suggested that the early
events in immune dysfunction could be prevented,
reversed or treated [22, 37–39, 45].
In summary, lack of systematic studies on multistep
carcinogenesis and the roles that inflammation play in
multistep carcinogenesis and concomitant generation of
cellular genetic instability and mutations in site-specific
tissues are primary scientific factors in failed therapeu-
tics. As recently suggested [22, 37, 38, 46–52, 57–65]
accumulation of ROS/RNS could significantly contribute
to the impaired mitochondrial function, changes in bio-
energetic that are required for maintenance of effective
immunity or the balance between two highly regulated
and biologically opposing arms termed Yin (tumoricidal)
vs Yang (tumorigenic) arms of acute inflammation [37].
It should be noted that the effect of ROS/RNS are addi-
tional damages on genetic components at random site.
In general, the claimed ‘molecular targeted’ therapies are
potent apoptotic factors that would initially inhibit one
or a combination of specifically designed growth factors
which temporarily cause ‘remission’ or growth-arresting
effects on tissues [22, 37–39, 62–66]. However, such
drugs would induce an ‘immune tsunami’ or ‘cytokine
storm’ throughout the body that destroy the structural
integrity and function of vital organs such as the liver,
kidneys, bone, muscle and vasculature with life-threaten-
ing side effects such as drug-resistant and cancer relapse,
cachexia, sarcopenia, thromboembolism, often resulting
in MOFs and death [18, 22, 62–65].
Chemotherapeutic approaches using low
molecular weight (LMW) agents: indiscriminate
drug‑distribution to normal and cancerous tissues
e standard or classic cancer chemotherapy, using low
molecular weight (LMW) drugs such as mitomycin C,
doxorubicin, methotrexate alone, or even in combina-
tion with other drugs for treating solid tumor have not
been successful. e toxicities of such drugs often dis-
tribute indiscriminately throughout the body with minor
tumor-selective accumulation. In addition, except for
preferential accumulation of doxorubicin in cardiac tis-
sue, majority of such LMW agents produce systemic
toxicity that damages various normal organs/tissues [33,
34, 54, 93–96]. Further increase in the drug dosage is
not possible since the dosage level is already at or near
their maximum tolerable levels as adverse effects would
appear at higher dose. e drug-induced systemic tox-
icities, in all likelihood, are due to the severe damages
to the functional and architectural integrities of tissues
such as biophysical, bioenergetics, mechanical organiza-
tions and physiology of vital organs leading to significant
Page 5 of 20
Maeda and Khatami Clin Trans Med (2018) 7:11
destruction (suppression) of immune system includ-
ing damages to bone marrow regenerative processes.
e overall toxicities of such drugs on the metabolic
and detoxification processes could progressively lead to
severe damages to the function of normal organs such as
the kidneys, liver, and heart, and it could further involve
in coagulopathy and peripheral neuronal toxicity, as well
as induction of diarrhea and bleeding.
It should be noted that with the exceptional effect of
chemotherapy on seminoma as solid tumors, the classic
anticancer drugs such as vinblastine, etoposide, bleo-
mycin, adriamycin, cis-platinum, etc., are yielding more
than 40–50% responses [84]. While the basis for this
remarkable response is not clearly understood, focus-
ing on such approaches may provide better direction for
future drug development. Also the effect of BCG with
combination of doxorubicin for bladder cancer has been
accepted with response rate of more than 50% [79, 97,
98].
e effectiveness of these drugs perhaps is due, in part,
to their influence on interdependent growth pathways
of phosphatidylinositol 3-kinase (PI3 K)/AKT/mTOR,
mammalian target of rapamycin and/or the suppres-
sive effects of interleukin receptor activated kinase-M
(IRAK-M) that cause induction of tolerance and growth
promotion [22, 37–39, 65]. In addition, drug-induced
increased immune suppression in patients facilitates can-
cer cells to further escape the immune system, resulting
in enhanced growth promotion and cancer relapse and
metastasis. e adverse effects of erythrocytopenia are
often treated with erythropoietin. However, concerns on
the induction of thrombosis cannot be ignored. Alter-
natively, red blood cell transfusion or iron supplement
are used to treat erythrocytopenia [2, 3, 70]. Although,
leukocytopenia are reasonably treated with granulocyte
colony stimulating factor (G-CSF), other drug-induced
systemic complications are difficult to control. Quanti-
fying and understanding the molecular/cellular bases of
drug toxicity invivo such as anorexia, cachexia, sarcope-
nia, bone-marrow suppression, fatigue or weakness, diar-
rhea, discomfort and pain are yet to be defined as these
complications are as important factors in the induction
of MOFs and increased morbidity and mortalities in
patients, particularly at the progressive stages of the dis-
ease [2, 3, 18, 22, 36, 37, 43].
Targeting genetic mutations in site‑specific solid
cancers that produced repeatedly failed outcomes
while generated huge corporate profits
Molecular target drugs created great business motives for
drug industry to focus on them in the last six decades.
After revealing extremely high incidence of mutations in
solid cancer (Table1), very little scientific rationale has
been presented for developing such costly molecular tar-
get drugs that are based on identification of too many
evolving genetic mutations in the chaotic cancer environ-
ments. Use of fashionable words such as ‘targeted’ thera-
pies, ‘personalized’ or ‘precision’ medicine are attractive
for drumming up the support of policy makers and the
public while highly lucrative for the decision makers
[14–19, 21–24, 26–31, 37, 39, 44, 45, 65, 66] (see footnote
3–7).
One should keep in mind the followings basic biologi-
cal events that occur in health and disease states of body’s
organ systems:
a. During normal oxidative metabolism of cell/tissue
and function, accidental chemical modifications or
genetic errors occur at the rate above 10,000 errors
alone in single cell even in the absence of external
genotoxic compounds [25–27, 35]. Concerns for cel-
lular mutations that would lead to carcinogenesis
often occur when combination of depyrimidination
or deamination of cytosine or 5-methylcytosine ade-
nine, guanine and related oxidation damages are at
rates that are much higher than 10,000 base per cell
per day [27].
b. In general, chemical carcinogenesis or mutagenic
chemicals interact with DNA or cross-link with seg-
ments of DNA, and directly impair DNA replication.
Maeda’s group found that chemical carcinogenesis
generates ROS or RNS via P-450 related enzymes
(e.g., cytochrome P-450 reductase). In this system
nitroguanosine acts as substrate to cytochrome b5
reductase or other NADPH reductase-like enzymes
(including NO synthase) and generate O2
·−, that
further trigger activation of NO synthesis, leading
to generation of ONOO− (peroxynitrite) for effec-
tive generation of DNA nitrateguanine that would
amplify reaction mechanisms (Fig.1) [49, 56, 57].
Table 1 Mutation rate in human cancers Adapted and
modified from Refs. [10, 25, 35].
Mutations of tumor cells were based on means of mutation in single patients
(CML/AML/ALL/CLL) Soft tissue/rhadomyoscarcoma
Cancer type Mutation/tumor
Respiratory/lung cancer 200–300
Skin/melanoma 100–200
Esophageal/colon cancer 50–100
Pancreatic, ovarian 30–60
Breast 20–70
Hematopoietic cancer 1–10
(CML/AML/ALL/CLL) rhabdo/myo/sarcoma 1–3
Page 6 of 20
Maeda and Khatami Clin Trans Med (2018) 7:11
In general, chemical carcinogenesis or mutagenic
chemicals interact with DNA or cross-link with segments
of DNA, and directly impair DNA replication. Maeda’s
group found that chemical carcinogenesis generates
ROS or RNS via P-450 related exnymes (e.g., cytochrome
P-450 reductase b. In this system nitroguanosine acts as
substrate to cytochrome b5 reductase or other NADPH
reductase-like enzymes (including NO synthase) and
generate O2
·−, that further trigger activation of NO syn-
thesis, leading to generation of ONOO− (peroxynitrite)
for effective generation of DNA nitrateguanine that
would amplify reaction mechanisms (Fig.1) [49, 56, 57].
Figure1 represents that NO-dependent viral mutant-
formation per 500 plaque in B6 mice, showing green
fluorescence protein (GFP)-encoded with Sendai virus
infection, resulted in increase of nonfluorescent viral
plaque in the lung. is event was compared with
iNOS-knockout mice (Fig.1d) [51, 59]. In addition, Mae-
da’s group demonstrated similar superoxide generation
from highly potent mutagenic heterocyclic amines [99–
101]. e observations further support the endogenous
generation of ROS and RNS, in addition to direct inter-
calation with DNA and damages to other metabolic and
bioenergetic pathways (see above) [22, 45, 65–69, 71].
e following are highlights of multistep carcinogene-
sis and current treatment approaches to cancer in experi-
mental and clinical studies:
a. e process of carcinogenesis with evolving muta-
tions at multi-stages of cell growth often take any-
where between 10 and 30years in human before tak-
ing over the machinery of dysfunctional immunity.
Oxidative stress during aging process that would lead
to immune dysfunction could cause generation and
CaM
FMN FAD Heme
NADPH
NADP+
NO
L-Arg
L-Cit
Reductase domain
Oxidase domain
e
-
e-
O
2
O
2•−
ONOO −
Guo
NitroGuo
• −
e-
EPR effect
NitroGuo
NOS
Days after infection
0
1.0
1.5
2.0
2.5
2467
1.5
B6
iNOS-/-
* *
* *
*
Increase in mutation rate (%
)
ab
d
c
Fig. 1 Generation of free radicals by infection and by heterocyclic amine (HCA), and generation of nitrated bases and mutation in Sendai virus via
NO. Pathways a, c and d are involved in infection-induced inflamed tissue involving induction of inducible form of nitric oxide synthase (iNOS), and
subsequently generation of nitric oxide (NO) and superoxide (O2
·−) and then peroxynitrite (ONOO−), which nitrated guanine (→ 8-nitroguanine),
and 8-nitroguanosine (NitroGuo), as substrates of NOS or cytochrome c reductase, thereby generation of O2
·−. The total system progressively pro-
duces O2
·−, with stoichiometry of greater than 1:1 [51, 100, 108]. b Generation of O2
·− from heterocyclic amine (HCA) in the presence of cytochrome
(Cyt) P450 reductase and NADPH, resulting in DNA damage, cleavage and mutation. c NADPH cytochrome P450 reductase would generates
O2
·− most effectively from nitroguanosine among other base-modified derivatives [57–61]. d Shows the NO dependence of viral mutation. *, **,
significant changes in % viral mutations in B6 mice, in comparison with iNOS knockout mice by time. ** statistical significance (< 0.01). See text
Page 7 of 20
Maeda and Khatami Clin Trans Med (2018) 7:11
accumulation of unrepaired genetic alterations lead-
ing to accelerated cell growth. As recently described,
cancer cell enhanced growth requirements are satis-
fied under loss of balance in Yin–Yang of immunity
that are associated with differential bioenergetic
requirements from mitochondria for oxidative phos-
phorylation leading to mitophagy and autophagy
and hypoxic conditions. e enhanced activities of
glycolytic pathways for inefficient energy production
(ATP) facilitate growth pathways (tumorigenic or
Yang) of immunity [22, 37, 38, 44, 62–65].
b. Advances in DNA sequencing technologies indi-
cate that the average patient with site-specific solid
tumors such as lung cancer, would have non-syn-
onymous 200–300 mutations per tumor in single
patient, while patients with esophageal, breast or
colon cancer had somewhere between 50 and 500
mutations per tumor (Table 1) [10, 22, 25–27, 35].
Consequently, making decisions on such evolving
high rates of mutations in human solid tumors make
these approaches fraudulent (‘molecular false flags’)
and irresponsible as evident from the high failure
rate outcomes of ‘molecular target’ therapies [18, 22,
36–38, 44, 65]. e claimed molecular target drugs
that aim at one or two specific mutations of growth
factors, receptors, or enzymes, whether or not the
mutations are at “driver seat” at the time they are
identified would maximally have 1–3% chances of
therapeutic success [29–34, 67, 68]. In addition, such
incredibly worthless projects totally dismiss the bio-
logical compensatory molecular events of body [18,
22, 33–38]. For example, clinical trials using combi-
nation of two inhibitors of EGFR for treating colon
cancer did not improve the efficacy compared with
single agent, and they are not remarkably different
from treating with conventional LMW drugs (shown
above). erefore, it is reasonable to conclude that
molecular targeted drugs based on identification of
one or few mutated genes or their expression prod-
ucts in the chaotic molecular landscape of cancers
(cancer molecular tsunami) would produce very lit-
tle to benefit the patients. It is not surprising that the
outcomes of such expensive undertakings have fail-
ure rates ranging between 85 and 95% while causing
life-threatening side-effects for patients and drain-
ing resources [4–6, 9, 10, 18, 22–29, 33, 34, 37–39,
63–65]. Analyses of similar data on cancer targeted
therapies that apply combination drugs such as
dasatinib, gemcitabine or debrafenive (debrafenib, or
Tafinlar) alone vs. debrafenive + trametinib (Meki-
nist), for treatment of advanced biliary tract or lung
cancers or metastatic melanoma show improved
progression-free survival of only few months (8.8 v
9.3 mons or 11.4 v 7.3 mons) while the agents cause
serious side effects. ese are examples of marginal
effects that are economically very costly with tremen-
dous patients suffering [12, 14, 16, 18, 21, 22–25, 70].
c. e inherent and diverse compensatory mechanisms
of immune and non-immune systems (e.g., vascula-
ture, metabolic and neuronal pathways) in patients
treated with specific growth factor inhibition could
induce expression of other growth factors locally
and/or systemically that would lead to anemia, cancer
relapse and metastasis [6, 18, 22, 34–39, 45, 48, 52,
62–65, 70]. Preliminary observations in experimental
model of mouse tumors demonstrated that block-
ing VEGF by antibody caused suppression of tumor
growth. However, as treatment with antibody discon-
tinued, tumor growth resumed at similar rate (Maeda
etal., unpublished data) suggesting antibody require-
ments to continue for unlimited period and long-
term results may not be beneficiary anyway. Hyper-
mutations occur more commonly and frequently in
solid tumors, compared with soft tissue cancers and
hematopoietic cells (Table 1) [5, 10, 17, 22, 25–27,
35–37, 45]. e latter has a very limited number of
mutations and thus respond with higher degrees
toward drugs such as Gleevec (imatinib), an inhibi-
tor of protein tyrosine kinase for treating chronic
myelogenous leukemia. However, even Gleevec-
treated patients suffer from drug-resistant as the
consequence of DNA mutations in the treated host
at later stages. Recently many drugs developed for
Gleevec-resistant patients have considerable success.
Although it is an endless game but worth to pursue
for better therapeutic for ultimate cure. While these
efforts to control the drug-resistance to Gleevec may
be encouraging, major motives behind such efforts,
seem economical [5]. Furthermore, mogamulizumab,
a monoclonal antibody against adult T cell leukemia/
lymphoma (ATL) was reported much less effective,
compared with imatinib. Currently, the effective-
ness of mogamulizumab that is used in combination
with conventional anti-leukemic agents makes inter-
pretations of its true efficacy difficult [80]. Similarly,
agents such as ipilimumab, that inhibit CTLA-4 for
melanoma treatment, and nivolumab that inhibits
PD-1 used for treating non-small cell lung cancer,
melanoma and renal carcinoma have limited suc-
cess (20–30% response rate) although drug-induced
autoimmune diseases is a major concern [22, 36, 44,
76–79, 81–83].
erefore, correction of genetic errors and mismatches
are normally required for adequate molecular repair
function at DNA and/or miRNA levels that also influence
Page 8 of 20
Maeda and Khatami Clin Trans Med (2018) 7:11
post translational modifications throughout life. It is
anticipated that if the number of chemical modifica-
tions on genome were to be excessive than normal under
such conditions as exposures to infective agents, chronic
inflammation, environmental, chemical or biological
hazards, as well as pathogen-specific vaccines or drug-
induced toxicity, particularly during aging, accumula-
tion of defective cells and proteins (e.g., cancerous cells,
non-functional proteins, senescent cells) create ‘antigen
over load’ that would retard effective immunity, to vary-
ing degrees, leading to altered immune response profiles
[18, 22, 27, 37–39, 44, 45, 48, 56, 62–66]. As detailed else-
where, sustained oxidative stress and loss of balance in
Yin and Yang of effective immunity could promotes accu-
mulation of molecular errors in tissues and increased
damages to genomic stability [22, 44, 45, 52–66]. Oxida-
tive stress-induced accumulation of genetic errors would
lead to expression and co-expression of growth and apop-
totic factors in susceptible tissues and create an ‘immune
tsunami’ that further skew and alter bioenergetics, meta-
bolic, hormonal and neuronal activities in susceptible tis-
sues toward multistep carcinogenesis [18, 22, 62–65].
In summary, the designs of effective cancer clinical
immunotherapeutic studies await acceptance of decision
makers in cancer community that the inherent immune
(cancer) surveillance that was recently defined as the
balance between dual properties of Yin (tumoricidal)
and Yang (tumorigenic) arms of effective immunity [18,
22, 44, 45, 62–65]. When immune surveillance loses its
ability to arrest the growth of oncogenic (defective) cells,
cancerous cells progressively and continuously mutate
throughout multistep developmental phases of tumo-
rigenesis, carcinogenesis and angiogenesis in susceptible
tissues. e results would be progressive expression and
co-expression of mismatched and unresolved growth-
arresting (Yin, or tumoricidal) and growth-promoting
(Yang, or tumorigenic) factors in the immune-responsive
tissues (e.g., epithelial-mesenchymal, stroma, vascular
endothelial). Unresolved inflammation would facilitate
immune evasion and growth promotion of such cells/
tissues toward the induction of neoplasia, pre-cancer
polyp-formation, cancer, angiogenesis and metastasis
[18, 22, 37–39, 44, 45, 62–65].
Cancer immunotherapy: better logics, same
reductionist approaches: controversial
understanding of immunity and inflammation
Over the last few decades, cancer immunotherapy,
including stem cell transplantation have emerged as the
choice for curing cancer on the assumption that cancer
cells possessing one or more new antigenic epitopes that
could provoke immunological responses, similar to those
of immune surveillance in normal host [5, 16, 22, 33, 34,
36, 65, 73, 74]. However, there is no dispute that cancer
patients are immune compromised, to varying degrees [5,
16, 22, 33, 34, 52, 62–66, 83, 85–87]. e early approaches
on cell-dependent immunotherapies were reported about
40years ago in mouse tumor models utilizing iv infusion
of invitro activated cultured T cells or LAK cells into the
host [85–87]. In these experimental settings, the treat-
ment was successful only when the number of effector
cells (E), that is cytotoxic T-cells (CTC) and natural killer
cell (NKs) was 30- to 50-fold greater than the number of
target tumor cells (T); that is, an E/T ratio of 30 or more
was required for tumor regression. However, tumors in
human frequently weigh 5–10 g or more. erefore, it
will require 150–300 g of activated T- or NK-cells for
infusion. Such approach is therefore unrealistic for treat-
ment of cancer patients. Although this treatment has not
been approved by Japanese National Health Insurance,
it is still performed in Japan and perhaps other cancer
treatment centers around the world.
In cancer immunotherapy, adaptive and innate immune
cells such as cytotoxic T cells (CTCs), natural killer cells
(NKs) and dendritic cells (DCs) are applied to target T-
or B-cell surface receptor molecules with the goal to treat
site-specific cancers [22, 64, 66–71]. However, actual
success in such approaches requires fundamental under-
standing of their use and identification and resolution of
the current biological gaps that hinder effectiveness of
treatment. e important knowledge gaps include iden-
tification of composition of host/target immune and non-
immune cells, interactions and synergies between host
and target tumor cells and understanding of the local
and systemic responses that would be involved in specific
treatment modalities [18, 22, 39, 44, 45, 65]. One should
keep in mind that the outcomes of treatment method-
ologies using antibody-like molecules that mimic T-cell
receptors (TCRs) on host T cell surface proteins that
would suppress or arrest the growth; or applying lym-
phocyte-activated killer cells (LAK) may be different in
different site-specific tissues. For example, lung airways,
gut-associated lymphoid tissues (GALTs) or conjunctival-
associated lymphoid tissues (CALTs) have immunologi-
cal features that are different from those in liver, stomach,
pancreas or non-muscle bladder tissues that potentially
contribute to unsuccessful treatment or drug delivery
technologies [18, 22, 37–39, 65, 66, 89, 93]. As such, the
tremendous knowledge gaps on cellular compositions
of target tissues and interactions, or synergies between
host tissue and treatment options are likely to limit the
effectiveness of such approaches [18, 22, 37–44, 62–65].
Furthermore, jury is still out on the outcomes and effec-
tiveness of stem cell therapy and bone marrow trans-
plant that are used for treating myelocytic leukemia on
patients pre-treated with whole body radiation to destroy
Page 9 of 20
Maeda and Khatami Clin Trans Med (2018) 7:11
majority of mutated blood cells. It should be noted that
clinical effectiveness of using the overall immune acti-
vation by application of bacterial cell components (i.e.,
BCG) into the urinary bladder tract for bladder cancer
seems a more logical approach as a worldwide estab-
lished method [79, 97, 98]. However, even BCG has its
adverse biological effects [22, 28, 39, 42–45, 97, 98].
Problem of liposomal and micellar drugs.
Controversies in stability and drug release
from liposomal or micellar complex of antitumor
drugs in tumor accumulation
Nanoparticle tumor targeting or delivery is based on
the enhanced permeability and retention (EPR) effect
[94–115]. EPR effect is a hallmark for targeted drug deliv-
ery of biocompatible nanomedicine or macromolecular
drugs in tumor tissue [53, 96, 99, 103–109]. e effect
can be observed in both primary and metastatic tumors.
e EPR effect can be visualized invivo tumor models or
human tumors [99, 108]. e EPR effect reflects patho-
physiology of solid tumor including defective vascular
architecture, upregulated neoangiogenesis and excessive
production of various vascular mediators. It is notewor-
thy that these factors are common immune disruptors
and contribute to the immune dysfunction.
Evaluation of some drug encapsulated liposomes and
micellar nanoparticles reveal another example of failed
attempts in cancer chemotherapy. Nanotechnology-
based nanomedicine has been the focus of great attention
in the past couple of decades. Initially, liposome particles
presented the poorest outcomes in the pharmacokinet-
ics because of little considerations of the rapid clearance
and removal of nanoparticles by phagocytic cells. How-
ever, current methods of attaching biocompatible poly-
mers such as polyethylene glycol (PEG) to the surface of
particles potentially protect them against this problem.
However, in the invivo setting, it is important that drug-
encapsulated liposomes or nanoparticles remain stable
and intact enough to reach to the target tissues without
disruption of particles or micelles on its way to reach can-
cer clumps. Otherwise, the active component of LMW
drug would often leak out from such particles during cir-
culation and subject to rapid clearance by urinary tract
or lymphatic channels, as well as potential decomposi-
tion by the liver and the bile. e possibility that particles
would burst before reaching the target make such drugs
to lose effectiveness while producing adverse effects
similar to the parental LMW drug given iv as shown in
Fig.2a, b. In contrast, rigid or sturdy structures of stable
particulate drugs such as Doxil®, a pegylated liposome-
containing doxorubicin (DOX) are too stable and exhibit
poor active-drug-release at the tumor tissue or reaching
the tumor while resulting poor clinical outcomes [33,
110–112]. As demonstrated in Fig.1b the iv injection of
unstable micellar drug-complexes will be physically dis-
rupted during circulation causing rapid release of the
free drug into plasma with no time to achieve EPR effect,
which is a time-dependent process. In contrast, cova-
lently linked nanodrugs or micellar drugs have better
plasma stabilities in vivo. Figure1, demonstrates range
of plasma concentrations of LMW free drug, such as free
DOX or pirarubicin (THP) in respective polymer com-
plexes invivo.
e use of micellar drug (e.g., NK-911) (Fig.1b) failed
at an early clinical stage due to its insufficient stability, as
it bursts too rapidly; losing nearly 50% of its concentra-
tion within 1h after iv injection, and producing no bene-
fit of the required EPR effect [113]. e same logics apply
for another biocompatible polymer DOX-conjugates, i.e.,
HPMA polymer-DOX conjugate (PK1), ~30kDa molec-
ular size, which failed to produce adequate circulation
time required for EPR effect [93–95, 103, 104, 107, 110].
In general, polymers with apparent molecular weight of
less than 40kDa would be too small to produce any effec-
tive EPR effect for tumor targeting.
Another example of confusing outcome is a drug
designed for macromolecular size, based on the EPR
effect for tumor-selective accumulation. In this approach,
Fig. 2 Schematic representation of plasma concentration of different
molecular size drugs [33, 34]: a low-MW free drugs (e.g., doxorubicin,
DOX) and b–e their polymer complexes. The drug concentration
in plasma after i.v. injection of low-MW drugs decreases rapidly (a).
Representative polymer conjugates, micelles, and the liposomal drug
(DOX) complex remain in the plasma at higher levels (b–e). However
(b) shows a micellar drug of non-covalently encapsulated low MW
drug which burst rapidly. Thus, no therapeutic benefit due to the EPR
effect as its stability is too poor; (c) a styrene-co-maleic acid (SMA)-
polymer covalent conjugate having better relative stability [103, 105];
(d) a more biocompatible polymer (HPMA) of pirarubicin conjugate
[34]; (e) highly stable and biocompatible liposome complex such as
Doxil®, showing high concentration in plasma for long period. This
stable liposome complex is a pegylated stealth liposome. However,
it is too stable and thus little drug release even after reaching to the
target tumor, and thus only a limited therapeutic effect. Nano-size
drugs (c–e) of high biocompatibility, having long plasma half-lifer, are
advantageous for tumor selective targeting because they can utilize
the EPR effect [33, 34]
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Maeda and Khatami Clin Trans Med (2018) 7:11
the miceller agent, fluorescein isothiocyanate (FITC) is
covalently linked to a polymer-carrier, while the micelle
also contained non-covalently encapsulated candidate-
drug (tritiated paclitaxel [PAX]) [99, 104, 107]. e
in vivo results showed accumulation of PAX at tumor
site was close to null. e non-covalently encapsulated
low MW PAX could leak out rapidly from the micelles in
the presence of NaCl or blood. However, had paclitaxel
covalently linked to the polymer it would have selectively
accumulated in the tumor site, as seen in FITC conju-
gated polymer-chain as the proof of the EPR effect [102,
107].
erefore, designing effective macromolecular drug
complexes requires considerations to include that the
selected drugs are stable enough and possesses sufficient
biocompatible property, with effective tumor accumu-
lation by EPR effect of the targeted tumors. After deliv-
ery in tumor tissue, appropriate drug release need to be
incorporated in such drug-complexed nanoparticles [33,
34, 53, 102].
In summary, despite decades of enthusiasm for nano-
medicine including liposomal, micellar and polymeric
drug complex, there are several problems that need to
be addressed. To be effective, such molecular complexes
should possess special features, including:
a. Retain at high levels in plasma for adequate duration
(several hours to a few days) having suitable biocom-
patibility to be utilized for EPR effect;
b. Molecular weights (MW) of macromolecules be
above 40kDa (above renal threshold);
c. Complexes would be capable of clearance by lym-
phatic system in normal tissues, in contrast to can-
cerous tissue; and
d. Complexes capable of extravasations at the tumor’s
‘leaky’ vasculature (angiogenic) sites while allowing
adequate liberation of free drug (AP’s) at tumor site,
via potential accessible or up-regulated membrane
transporter systems (cell-uptake) on tumor cells [33,
34, 102].
Furthermore, there are great differences on cellular
uptake rates of different low MW drugs. For example,
free pirarubicin (THP) exhibits over 30- to 100-folds
higher cellular uptake into tumor cells (pancreatic SUIT-
2) compared with free DOX, although both belong to
the anthracycline family in which a specific transporter
system (e.g., glucose transporter) is highly up-regulated
for THP uptake in some tumor cells [95, 102, 114]. ere-
fore, application of polymer-THP-conjugates seems more
advantageous compared with polymer-DOX-conjugates.
Problems with cancer drug screening and safety
in rats and mice: limitations for clinical efficacy
in human
Details of the problematic issues in cancer drug discov-
ery and screening methods using experimental mice or
rats models of site-specific tumors have been recently
reported [22, 44, 115–121]. e major concerns on drug
screening are safety and therapeutic efficacies, as well as
ethical and financial considerations of decision makers
who apply the results that are produced in small animal
models in clinical trials to test various anticancer agents
in patients which repeatedly failed. e principal con-
cerns with the use of anticancer drugs in clinical trials are
briefly discussed below:
a. Traditionally, drug development for chronic diseases
(e.g., diabetes, hepatitis C, malaria or HIV/AIDS)
used chimpanzees as experimental models of human
diseases and for drug evaluation purposes. ese pri-
mates are genetically, behaviorally and biologically
the closest animal species to humans. However, in the
last few decades, nearly all experimental models of
cancer drug screening, safety and efficacy evaluation
are performed in lower animals such as rats and mice.
e drug screening, efficacy and toxicity of candidate
drugs, e.g., monoclonal antibodies against specific
growth factors, inhibitors of receptor molecules or
kinases, are performed by nu/nu genetic engineered
animals, primarily in mice, tissue cultures, or in test
tubes, but usually not in chemically-induced autoch-
thonous models. Consequently, as expected the phar-
macokinetic parameters or compatibilities of the
drugs tested in lower animals are vastly different from
those in cancer patients with regard to time scale and
immunobiological response profiles and tolerance
[22–24, 44, 115–117, 121]. For example, drug screen-
ings are routinely tested in mouse peritoneal leuke-
mia L1210 and P388 models. In such studies, tumors
are implanted intraperitoneally (ip), and the drugs
also administered via the same route. In such cases,
a given drug is likely to be readily accessible to tumor
cells in the peritoneal cavity. Under these conditions,
pharmacological properties of drugs such as plasma
level, tissue distribution, inactivation or clearance
from the liver and kidney, and access to vasculature
do not pose any serious problem. Consequently, in
the ip (tumor)/ip (drug) system, one might demon-
strate the desired immediate drug action in tumor
cells. ese traditional approaches, although bet-
ter than screening invitro tumor-cell-panels, totally
ignore and downplay the complexity of human solid
Page 11 of 20
Maeda and Khatami Clin Trans Med (2018) 7:11
tumors with complex cellular, stromal or matrix and
vascular architectural features of the tumor micro-
environment including the neoangiogenesis and
vascular permeability, hypoxia, low pH, induction of
altered immune and non-immune response dynam-
ics, various proteases that cancer cells excrete, coagu-
lation and cellular clumps of disorganized adhesion
properties of cancer cells.
b. e anatomical sites used for implanted tumors in
mice and the role that vasculature plays will pose
differences in efficacies. Implanted tumors are fre-
quently located in the skin or muscle at early stage
of development, and not in the orthotopic sites for
the primary cancer sites. As a result, one may reason-
ably question such tests since the drug access to vas-
culature in experimentally selected sites (e.g., skin)
in mice or rats, differ from those cancers developed
in the lung, kidney or liver even in mice, let alone in
patients which have complex multi-layered archi-
tectural organizations and anatomy [115–117]. It is
worth emphasizing that even renal cancer cells or
hepatoma cells implanted in the muscle tissue of mice
do not possess the same features of vascular network,
comparable to the kidney or the liver, respectively. In
addition, metastatic tumor models are rarely used for
drug screening purposes, although it should be the
focus of testing if the purpose of screening is the con-
trol of advanced stages of cancer [115–117].
c. Another problem is the mouse model itself, which
is usually a syngeneic system or nude mouse model,
when used for studying human xenograft system.
Except for identical twins, there are no syngeneic
humans. In the syngeneic mouse model, the human
tumors (xenobiotic) usually exhibit immunologi-
cal compatibility with the host mice. erefore, a
host reaction to a xenobiotic tumor is often absent
because the tumor would be immunologically inert.
Furthermore, the mice implanted with human xeno-
graft tumors do not react immunologically as do
the human tumors. In addition, the time scale for
tumor development between human and mice are
not comparable at all. e so-called window model,
using implanted solid tumor in a confined space, i.e.,
squeezed between two plates of Lucite, is only appli-
cable for very limited cases as tumor is physically
so compressed in a confined space and the physical
pressure will be built up as artifact. For these reasons,
such tumor models represent artifacts, particularly
because the doubling time of rodent tumors is so
short that it will quickly and physically saturate the
space, hence tumor-induced interstitial pressures
will be compressed and are not at all comparable to
human tumor growth.
d. Experimental mouse tumors grow rapidly; that is
not usually the case with human tumors. Implants of
5×106 tumor cells in a mouse reach a palpable size
in about a week or so, whereas human tumors often
take months or years to reach a sizeable tumor. ere
also are 10- to 50-fold differences in doubling time for
tumor growth; a few days in mice, and 30–100days
in human. erefore, relatively fast release of drug
from nanoconstructs or liposomes will be found best
rate for drugs in mouse system but not suitable for
patients.
e. e most common endpoint of drug screening sys-
tem in mice is prolongation of survival rate but not
the cure rate, when compared with control group
receiving no drugs, in which all mice in test group
would eventually die. Complete cure with anticancer
agents; claimed ‘targeted’ therapy, ‘precision’ or ‘per-
sonalized’ medicine is rarely known, particularly with
metastatic solid tumors. e endpoints of cure rate
with longer period of more than 100days in mice,
with no recurrence of tumor rarely seen. Investiga-
tors should adapt a model that is comparable to the
antibiotic-drug-development for infectious diseases
decades ago.
In summary, autochthonous or chemically induced
models of breast, colon, or liver cancers may offer more
realistic tumor models, compared with transplanted syn-
geneic tumor models. e drug screening designs have
little/no considerations for the effect of drug against
metastatic tumors, which is by far the most critically
important and formidable stage of disease that spreads
to distant sites, often beyond surgical removal, while
the primary tumor can often be successfully removed
by surgery. In general, using mice model may be some-
what more suitable for drug tests for HIV/AIDS patients,
having specific immunological response (e.g., T cells)
complications to overcome, when compared with can-
cer patients with multistep immunobiological, meta-
bolic, neuronal and cellular complications. As detailed
in recent reports, cancer patients primarily suffer from
the severe loss of effective immunity or the balance
between Yin (tumoricidal) versus Yang (tumorigenic)
properties of immune system that involve loss of oxida-
tive phosphorylation and bioenergetics in mitochondria
(mitophagy), enhanced metabolism of glucose (e.g., War-
burg glycolysis), loss of cell contact inhibition and altered
architectural integrity of site-specific tissues which are
advantageous for parasitic survival of cancer cells [22,
44, 45, 62–66]. As proposed below, the above scientific
concerns should be taken into consideration for effective
systemic chemotherapeutic approaches that could offer
serious hope for treating patients.
Page 12 of 20
Maeda and Khatami Clin Trans Med (2018) 7:11
Controversies and bias in conducting clinical trials:
over‑diagnosis, crossovers and randomization
of protocols
Patient eligibility to enter the clinical trials most fre-
quently involves stages I and II of the disease. As recently
reported [6–9], stage I or even stage II diagnosis for can-
cer patients are often over-diagnosed. In general, adverse
effects of drugs in healthier population are less compared
with those observed in patients at advanced stages of the
diseases (stages III and IV). Furthermore, ethical con-
cerns and pitfalls regarding the crossover trials that allow
patients to switch from control to experimental arms, for
receiving investigational drugs remain a serious problem.
A reason is that the adverse effects of previously adminis-
tered drug could not be readily washed out in the body
within a month or so, therefore treating patients with a
second drug after 1month may be more hazardous [7–9,
13–17]8. e vast differences and bias in the randomized
trials using surgical procedures of site-specific cancers, as
well as the biological, pharmacological and intrinsic
activities of experimental drugs generated in the body
would make such crossover trials senseless, if not harm-
ful for the patients [7–9, (Khatami, manuscript in prepa-
ration)]. For example, sunitinib is an inhibitor of VEGF
for treating renal carcinoma, while iniparib is an inhibitor
of DNA polymerization and synthesis [poly(ADP-ribose)
polymerase (PARP)] for treating triple-negative breast
cancer. ese drugs have very different mechanisms of
action [3, 4, 6–10] (see footnote 8). Patients suffering
from advanced renal cell carcinoma, initially treated with
IFN-α might have improved survival outcomes from
crossover strategy with sunitinib, as both drugs have
potential additive effects in inhibiting VEGF [14–17].
However, using iniparib in crossover trials is not effective
for patients with triple-negative breast cancer [3]. One
should keep in mind that in general, PARP inhibitors (ini-
parib) lack intrinsic value for solid tumor. Such drugs are
ineffective for BRCA1 and BRCA2 mutations [3, 13–15].
e goal for treatment with iniparib in crossover trials
should be potentiating the activities of traditional ‘back-
bone’ drug in combination and beneficiary to the
patients, but they are not. For example, reports for trials
that use combination of gemcitabine plus carboplatin,
showed outcomes of progression-free survival of only
3.6 months reported for control arm (almost insignifi-
cant, and no cure). Furthermore, analyses of data on the
outcomes of crossover trials using iniparib, for its effect
on sensitization of temozolomide (bevacizumab) in glio-
blastoma xenograft or clinical targeted therapies of
advanced glioma are inconclusive [3, 14–16, 118–120].
8 Summary Health Statistics for U.S. Adults: CDC, National Health Inter-
view Survey (2011).
Photodynamic therapy (PDT). A century‑old history
and little tangible advancement
Photodynamic therapy (PDT) for treating diseases is
known for more than a century. Indeed, N.R. Finsen
received the Nobel Prize in Medicine and Physiology in
1903 for his novel phototherapy of dermal tuberculosis.
PDT was expanded to treat cancer about half a century
ago, as the use of helium-neon (He–Ne) laser that emits
monochromatic light at 633 nm became commercially
available. e key component required in PDT is excita-
tion of photosensitizers by appropriate wavelength in the
tumor tissue. Most of currently used photosensitizers are
derivatives of tetrapyrrolic compounds [121–124]. ey
require excitation-light around 400–450nm for optimal
effects [121–124]. For cancer treatment, penetration of
light (400–500nm) into cancer tissue is a prerequisite
to generate singlet oxygen (ROS). e currently applied
He–Ne laser light sources for PDT fail to fulfill the basic
principle of spectroscopy for crucial points:Commercial
photosensitizers for PDT such as Laserphyrin® and
Photofrin® have Soret band of absorption range that pro-
duce both intense fluorescence and singlet oxygen (1O2).
However, excitation by He/Ne laser, which emits only at
633nm, but does not emit at wavelength of 400–450nm,
thus not satisfy the optimal spectroscopic requirements
for most efficient generation of singlet oxygen for effec-
tive therapy [122]. It should also be mentioned that not
all tissues, particularly cancer tissues, are similarly loaded
with heme components, like in the normal liver, spleen
and blood. When the tissue surface of, for instance,
breast cancer is observed visually, or colon cancer by
endoscope, the solid tumors exhibit no reddish appear-
ance. As a matter of fact, when we used xenon light of
400–450nm range directly over the breast cancer it did
penetrate sufficient dose of light into the breast cancer in
rats, and cancer was completely eradicated (Fig.3c) [99,
108, 122, 123].As described above for EPR effect, the cur-
rently used photosensitizes use molecular weights less
than 1000Da [121–124]. us upon iv infusion, they are
distributed nearly indiscriminately throughout the body
[93, 94, 96, 103] providing no EPR effect and little tumor
selectivity. Figure3a, b represent results of macromolecu-
lar-model compound of photosensitizers for tumor selec-
tivity in comparison with low MW counter parts. Using
low MW photosensitizer, while producing no remarkable
antitumor effect, the patients are advised to avoid expo-
sure to ambient daylight as it is expected to damage the
skin with hypersensitivity reactions of the exposed areas.
On the contrary, when polymeric photosensitizer and
light source (around 430–450nm) irradiation were used
for rat breast cancer invivo, it produced clear fluorescent
tumor image and significant tumor regression [122–124].
Page 13 of 20
Maeda and Khatami Clin Trans Med (2018) 7:11
Prohibitive costs of cancer therapy with repeatedly
failed outcomes. Economic impact on medical
insurance, and unbearable burden to the society
A serious problem in current cancer chemotherapy
involves the cost of care for cancer patients, particu-
larly the astronomical costs of recently claimed molecu-
lar ‘targeted’ drug, ‘personalized’ or ‘precision’ medicine
with outcome failure rates of 85–95% [5, 22, 37, 39, 40,
44, 65, 66] (see footnote 1−8). While majority of such
drugs produced no reasonable benefit to meaningfully
extend survival of cancer patients, particularly those
with solid tumors, they are tremendously costly for the
patients, their families and the public [2–8, 13, 18, 20–22,
24, 32, 37, 39, 44, 65–67, 98, 125–127, 131, 132]. Cancer
‘designer’ drugs cost between $100,000–$1000,000 (USD)
per course of treatment. For example, nanomedicine type
Fig. 3 Superiority of macromolecular photosensitizer: a polymer (HPMA)-conjugated zinc protoporphyrin (ZnPP) and b bovine serum albumin
(BSA)-conjugated rhodamine. Fluorescence shows as visible only in tumors (a) and (b) (T marks). However, when both low MW photosensitizer, free
ZnPP (aʹ), and free tetramethylrhodamine (bʹ) in tumor-bearing mice are injected iv, no tumor selective fluorescence image was visible. Macromol-
ecules, namely polymer-(HPMA) ZnPP and BSA-rhodamine with apparent MWs about 50–70 kDa, respectively, selectively accumulated in tumors,
because of the EPR effect, as shown by in vivo fluorescent imaging system; Contrary to above, free ZnPP and free rhodamine, with MWs less than
1000 Da, showed little tumor uptake (aʹ, bʹ). c Demonstrates therapeutic effect of PDT-treatment using polymeric ZnPP and endoscopic xenon light
irradiation. Tumors used were chemically (diaminobenzene[α]anthracene) induced breast cancer in rats. Polymer-ZnPP alone or light irradiation
alone respectively has no therapeutic effect [99, 122] (Figures were adapted from Refs. [99, 122] with permission)
Page 14 of 20
Maeda and Khatami Clin Trans Med (2018) 7:11
anticancer agents such as Doxil® and Abraxian® cost on
average $5000 per injection, that is about 10 times the
cost of the parent drugs (doxorubicin and paclitaxel,
respectively), without significant survival benefit. e
drug makers’ ‘rational’ is that the complex drugs provide
more tolerable toxicity for Doxil® compared with free
doxorubicin! [125–127].
In the Japanese National Health Insurance System, all
patients are eligible to receive government-approved
medications and treatments. However, patients must pay
out-of-pocket for all medical and hospital costs, if any
unapproved medicines were used in conjunction with
ongoing/approved treatment. us, patients who use any
additional unapproved medications lose all privileges of
receiving the insurance benefits, even though the par-
ticular procedure could potentially provide the needed
therapy with proven benefit. For instance, concomitant
use of nitroglycerin together with low MW chemother-
apeutic agents, significantly benefits the patients with
marginal cost [126–130]. It is noteworthy that currently,
the total medical expenditure is near 90% of the Japanese
National income revenue in 2012 [131]. e government
is faced with decision, either to cut this heavy burden for
paying the ineffective therapeutic modalities, or alterna-
tively raise the public income-taxes. In the United States,
nearly half of the reported personal filings for bankruptcy
are due to high cost of medical care resulted from astro-
nomical cost of drugs, hospitalization, medical proce-
dures and patient care [22, 44, 125–127].
Concerned voices of independent and competent
professionals, oncologists and scientists that are raised
for seeking the truth in cancer science, on behalf of the
cancer-stricken public for changing the directions in can-
cer research or therapy or safety and unethical motives
behind development of pathogen-specific vaccines (e.g.,
HPV, flu, meningitis) that repeatedly failed cannot be
ignored or silenced any longer by policy/decision mak-
ers [2, 21, 22, 44, 65, 66, 125, 127]. To lessen the heavy
burden of costs, for Japanese complex insurance poli-
cies, we recommend that the unapproved but potentially
effective and safe drugs should become available to can-
cer patients. e public insurance system should remain
continuing coverage of the cost of those drugs that are
already approved and marketed for different indications,
while those who are willing to undergo treatment with
additional experimental drugs, pay out-of-pocket for the
cost of drugs that are yet to be approved. It is anticipated
that such methods of payment reduce the cost of care
for patients who need additional drugs, while the Japan
National Health Insurance System can avoid increased
debt. We also suggested that the USA policy makers
and medical/cancer establishment to return to ‘common
sense’ that our forefathers used to serve the public [22,
39, 44, 66].
Future perspectives: logical, systematic
and cost‑effective approaches to cancer research
and therapy
Lack of systematic approaches to cancer biology is per-
haps the principal reason for the extremely slow progress
in understanding cancer science, evidenced by high fail-
ure rates in cancer therapy and associated loss of millions
of lives and tremendous economic burden to the society.
e approaches to drug development that are inhibitors
against specific growth factors, receptor-molecules or
enzymes and are identified in the chaotic and disordered
molecular environments of site-specific tumors or cur-
rent approaches to pathogen-specific vaccines are con-
sidered ‘molecular false flags’ based on false foundation.
ese worthless schemes remind us the USA congres-
sional debates of ‘building bridges to nowhere’ [18, 22, 37,
65, 66]. Decision makers of such thoughtless approaches
totally ignore biological consequents of body responses
and the extensive harms that are induced to immunity
when patients are treated with combination of total (or
partial) body radiation and targeted therapy (‘designer
drugs’) [18, 22, 39, 65, 66].
Recent paper by Prasad and colleagues [132] supports
our scientific concerns that despite reported reduction
in disease-specific mortality, the overall mortality was
unchanged or increased. Many cancer drugs would initi-
ate or accelerate other causes of death such as dissemi-
nated intravascular coagulation (DIC) and multiple organ
failures (MOFs) as the consequences of complications
such as extreme fatigue or infections, interstitial pneu-
monia, acute cardiac arrest or cachexia, often resulting in
loss of patients lives. Nearly all other claimed molecular
targeted therapies that are heavily publicized and funded,
focus on identification of infinite genetic mutations in
site-specific solid cancers, produced little, if any, success
to benefit cancer patients. Majority of such drugs that
often accompany total or partial body radiation therapy
produce biological poisons to the already immune-com-
promised patients. e drugs, not only produce life-
threatening side effects, but they are extremely costly for
patients and insurance companies.
Below we outline that future systematic approaches
to study the amazing complex role of immune disrup-
tors-induced initial immune dysfunction toward multi-
step carcinogenesis that are intimately associated with
angiogenesis (hallmark of tissue growth, hypoxia and
altered bioenergetics) offer tremendous opportunities for
research and therapeutic considerations [22, 36–39, 56,
65–67, 108, 126–154].
Page 15 of 20
Maeda and Khatami Clin Trans Med (2018) 7:11
a. Modalities that utilize nanotechnologies for tumor-
selective drug delivery, based on the EPR effect with
full consideration of tumor environments. Utiliza-
tion of tumor environments for tumor-selective drug
accumulation include the lower pH of tumor tissue
(1–1.5units) compared with normal tissue (pH 7.4).
In addition, the unique features of upregulated glu-
cose transporter in tumor provide good targets using
glycosyl-containing moiety for drug development.
Furthermore, hypoxia that is the result of embolized
blood flow in solid tumor vessels may be restored
by nitro agents or alike, to improve the blood flow
and drug delivery. Acidic environment of tumor
are suggested suitable site for EPR and cleavage by
hydrolytic enzymes (e.g., cathepsin, MMPs, etc.),
or spontaneous cleavage of acid labile bonding (e.g.,
hydrazone, ester bonds) between linker polymers and
desired drugs.
b. Systematic studies to understand immune disrup-
tors-(oxidative stress) induced initial pathways in
developmental phases of immune dysfunction in the
direction of multistep tumorigenesis and angiogen-
esis. Effective immunity was defined as the balance
between two highly regulated and biologically oppos-
ing arms, Yin (tumoricidal) and Yang (tumorigenic)
properties of acute inflammation, an amazingly pre-
cise signal communications between immune and
non-immune systems. e Yin and Yang events were
hypothesized requiring differential bioenergetics at
different stages of life, from fetus growth, after birth
toward adulthood and aging process or chronic dis-
eases. Unresolved inflammation was described as a
common denominator mapping aging process and
the induction of ‘mild’, ‘moderate’ or ‘severe’ immune
disorders including cancers. Detailed understanding
of the loss of balance in tumoricidal (Yin) and tumo-
rigenic (Yang) properties of effective immunity that
guards health should be the focus of future studies.
c. Details of pathogen-host interactions and immune
response profiles in susceptible tissues. We recently
proposed that chronic inflammation causes release of
histamine at local and distant tissues altering numer-
ous other immune responses and the acid-base
behaviors in tissues including vasculature. Histamine
was proposed as blue print in the genesis of ‘mild’,
‘moderate’ or ‘severe’ immune disorders including
site-specific cancers.
e above logical approaches to therapy and basic
research on complex biology of effective immunity are
expected to result in the design of cost-effective projects
for understanding not only the cancer biology or how to
prevent or control (treat) it, but also effective approaches
for development of universal vaccines and overall promo-
tion of health. Furthermore, systematic approaches in
understanding effective immunity are expected to lay a
foundation for minimizing or delaying the onset of nearly
all other chronic and preventable diseases for the aging
populations around the world [22, 36–39, 43–45, 65, 66].
Concluding remarks
e focus of this perspective was to assess the limita-
tions of current therapeutic approaches to cancer. We
presented scientific analyses of the disturbing data on the
outcome failure rates of 90% (±5) on current therapeutic
approaches for solid tumors. In the last six decades, only
limited success was achieved with drugs such as Gleevec
or few other modalities that used for treating patients
with hematopoietic cancers and soft tissue or seminoma.
e future logical directions for cancer science and
therapy to be beneficiary to the public should focus on
restoration of immune surveillance, the body’s protec-
tive mechanism for killing cancerous cells. e claimed
‘targeted’ therapies that may or may not extend remission
of cancer for a few months should not be accepted any
longer as ‘cure’ by oncologists, scientist or patients. ese
tremendously costly projects totally disregard the suf-
fering and life-altering experiences of patients and their
families or caregivers [18, 22, 28, 32, 37, 39, 44, 65, 66,
125–127, 154]. Torturous period of survival overwhelms
the benefit of postponing ‘death-sentence’ of patients
for few months. It is important to seriously consider
that the cost for conducting too many out-of-focus pro-
jects including usage of specific detection technologies
for ‘targeted’ or ‘designer’ drugs that repeatedly failed
patients has increased 340 time in the last 10years, while
accomplished very little. is horrendous view for mak-
ing profit out of misery of patients can no longer be sus-
tained or tolerated.
Another serious concern in process of drug develop-
ment, however wrong, is the long processes and delays
in obtaining patents, proprietary and approval for new
drugs. In most countries, exclusivity of proprietary for
marketing a specific drug often guaranteed for up to a
decades. We propose abolishing the currently imposed
regulations of drug patent system with the goal to accel-
erate generic drug development and improved access of
drugs to patients. Often the industry manages to extend
blocking the patented drugs for unlimited time, for main-
taining the marketed drug prices at sky high and for high
profits.
Abbreviations
ALL: acute lymphocytic leukemia; AML: acute myelogenous leukemia; BCR:
breakpoint cluster region; BRCA: hereditary breast cancer gene; CLL: chronic
lymphocytic leukemia; CML: chronic myelogenous leukemia; DIC: dissemi-
nated intravascular coagulation; DOX: doxorubicin; dTNFR: decoy receptor of
Page 16 of 20
Maeda and Khatami Clin Trans Med (2018) 7:11
tumor necrosis factor; EGF: epidermal growth factor; EPR: enhanced perme-
ability and retention; HPV: human papilloma virus; HPMA: N-(2-hydroxypropyl)
methacrylamide; iv: intravenous; LAK: lymphocyte-activated killer cells; LMW:
low molecular weight; MCs: mast cells; MMPs: matrix metalloproteinases; MOF:
multiple organ failure; NK: natural killer; NO: nitric oxide; NO2−: nitrite; O2
·−:
super oxide anion radical; PAX: paclitaxel; PDT: photodynamic therapy; PEG:
polyethylene glycol; PG: prostaglandin; PI3 K: phosphoinositol-3-kinase; PS:
photosensitizer; QOL: quality of life; RO: alkoxyl radical; ROO: alkylperoxyl radi-
cal; ROS: reactive oxygen species; SMA: styrene-co-maleic acid polymer; mTOR:
mammalian target of rapamycin; TCR: T cell receptor; THP: tetrahydropyranyl
doxorubicin (pirarubicin); TLRs: Toll like receptors; VEGF: vascular endothelial
growth factor; ZnPP: zinc protoporphyrin.
Authors’ contributions
HM and MK co-designed and wrote the manuscript, they both revised the
manuscript. Both authors read and approved the final manuscript.
Author details
1 BioDynamics Research Foundation, Kumamoto University (Med), Kumamoto,
Kenshin Bldg 3F, Kuwamizu 1-chome, 24-6, Chuo-ku, Kumamoto 862-0954,
Japan. 2 Osaka University Medical School, Osaka, Japan. 3 Tohoku University,
Sendai, Japan. 4 Inflammation, Aging and Cancer, National Cancer Institute,
The National Institutes of Health, Bethesda, MD, USA.
Acknowledgements
Laboratory studies of Mahin Khatami were established at the University
of Pennsylvania, School of Medicine, Department of Ophthalmology,
Philadelphia, PA; supported by NEI/NIH (RO1 EY03984, RO1 EY03984–05S1,
RO1 EYO1244–14S1) in 1980 s; detailed analyses of data were extended at
the National Cancer Institute (NCI), the National Institutes of Health (NIH),
Bethesda, MD since 1998, despite heavy opposition to promote the role of
inflammation in cancer research and therapy by upper managers at NCI/NIH.
Research Grants for Hiroshi Maeda were supported by the Ministry of Educa-
tion, Culture, Sports, Science and Technology (MEXT ), Japan, No. 17016076
for cancer specialty grant, AS242Z01542Q for A-STEP, and by the Ministry
of Health, Labor and Welfare (MLHW), Japan, No. 3rd Anticancer Research-
General 001.
Mahin Khatami has been retired from The National Institutes of Health
Competing interests
The authors declare that they have no competing interests.
Availability of data
Not applicable.
Ethics approval and consent to participate
Not applicable.
Funding
Provided as N/A.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in pub-
lished maps and institutional affiliations.
Received: 16 January 2018 Accepted: 31 January 2018
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