ArticlePDF Available

Active Hexose Correlated Compound (AHCC) Alleviates Gemcitabine-Induced Hematological Toxicity in Non-Tumor-Bearing Mice


Abstract and Figures

Active hexose correlated compound (AHCC) is known as a dietary supplement derived from an extract of a basidiomycete mushroom. The present study was conducted to evaluate the role of AHCC in alleviating the side effects, particularly hematological toxicity, in non-tumor-bearing mice receiving monotherapy with gemcitabine (GEM). The results from the GEM treatment groups with and without AHCC administration were compared to control group that received vehicle alone. The GEM alone treatment reduced peripheral leukocytes and hemoglobin, and bone marrow cell viability in spite of no influence on body weight, food consumption, and renal and hepatic parameters. Supplementation with AHCC significantly alleviated these side effects. The colony forming assay of bone marrow cells revealed that AHCC improved reduction of colony forming unit-granulocyte macrophage (CFU-GM) and burst forming unit-erythroid (BFU-E) related to GEM administration. However, when mRNA expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (EPO) was examined using a quantitative reverse transcription polymerase chain reaction (RT-PCR), AHCC showed no effect for the mRNA levels of their hematopoietic growth factors. These results support the concept that AHCC can be beneficial for cancer patients with GEM treatment through alleviating the hematotoxicity.
Content may be subject to copyright.
International Journal of Clinical Medicine, 2012, 3, 361-367 Published Online September 2012 ( 1
Active Hexose Correlated Compound (AHCC) Alleviates
Gemcitabine-Induced Hematological Toxicity in
Non-Tumor-Bearing Mice*
Daisuke Nakamoto, Kota Shigama, Hiroshi Nishioka#, Hajime Fujii
Amino Up Chemical Co., Ltd., Sapporo, Japan.
Received May 16th, 2012; revised June 17th, 2012; accepted July 16th, 2012
Active hexose correlated compound (AHCC) is known as a dietary supplement derived from an extract of a basidiomy-
cete mushroom. The present study was conducted to evaluate the role of AHCC in alleviating the side effects, particu-
larly hematological toxicity, in non-tumor-bearing mice receiving monotherapy with gemcitabine (GEM). The results
from the GEM treatment groups with and without AHCC administration were compared to control group that received
vehicle alone. The GEM alone treatment reduced peripheral leukocytes and hemoglobin, and bone marrow cell viability
in spite of no influence on body weight, food consumption, and renal and hepatic parameters. Supplementation with
AHCC significantly alleviated these side effects. The colony forming assay of bone marrow cells revealed that AHCC
improved reduction of colony forming unit-granulocyte macrophage (CFU-GM) and burst forming unit-erythroid
(BFU-E) related to GEM administration. However, when mRNA expression of granulocyte-macrophage colony-stimu-
lating factor (GM-CSF) and erythropoietin (EPO) was examined using a quantitative reverse transcription polymerase
chain reaction (RT-PCR), AHCC showed no effect for the mRNA levels of their hematopoietic growth factors. These
results support the concept that AHCC can be beneficial for cancer patients with GEM treatment through alleviating the
Keywords: Anticancer Drug; Bone Marrow Suppression; Colony Formation; Hemoglobin; Mushroom Extract; White
Blood Cells
1. Introduction
Gemcitabine (2’,2’-difluoro-2’-deoxycytidine, GEM), a
pyrimidine based nucleoside analog, [1] is metabolized
to gemcitabine diphosphate and triphosphate inside the
cell by nucleoside kinases [2]. Gemcitabine diphosphate
is a potent inhibitor of ribonucleotide reductase, which is
associated with deoxyribonucleotide pools [3]. A reduce-
tion of deoxyribonucleotide concentration leads to the
inhibition of DNA synthesis. Gemcitabine triphosphate
competes with deoxycytidine triphosphate (dCTP) in
binding to replicating DNA polymerases and then is in-
corporated into DNA to prevent further elongation of the
replicating strand, resulting from increase in the ratio of
cellular concentrations of gemcitabine triphosphate to
dCTP [4]. Thus, the major mechanism of action of GEM
is the direct or indirect inhibition of DNA synthesis.
In cancer therapy, GEM is commonly used as a com-
ponent of adjuvant chemotherapy for advanced pancre-
atic cancer [5]. Additionally GEM is also used for the
treatment of various other carcinomas such as non-small
cell lung cancer [6], ovarian cancer [7], breast cancer [8],
and biliary tract cancer [9]. The limited toxicity associ-
ated with GEM therapy compared to other cytotoxic
anticancer drugs is one of the major reasons for the
widespread use in chemotherapy. Although hematologi-
cal toxicity and flu-like symptoms caused by GEM are
the most common side effect, they are mild and short-
lived [10]. However, these toxicities related to GEM can
lower the quality of life in cancer patients and often trig-
ger reductions in the dosage, frequency and duration of
chemotherapy, ultimately decreasing potential for opti-
mal therapeutic outcomes.
An approach to relieve the side effects of anticancer
drugs including GEM leads to the use of complementary
and alternative medicine (CAM) that has attracted great
attention. Many cancer patients are currently using CAM
in order to reduce the side effects and obtain additional
chemotherapeutic effects through boosting the immune
system [11]. In Japan, 44.6 percent of cancer patients
*No competing financial interests exist.
#Corresponding author.
Copyright © 2012 SciRes. IJCM
Active Hexose Correlated Compound (AHCC) Alleviates Gemcitabine-Induced
Hematological Toxicity in Non-Tumor-Bearing Mice
reported using CAM with the most frequently used treat-
ment being dietary supplements of mushrooms such as
agaricus (Agaricus blazei Murill) and active hexose cor-
related compound (AHCC) [12].
AHCC is a mixture of polysaccharides, amino acids,
lipids and minerals derived from mycelial culture of the
basidiomycete, Lentinula edodes. The predominant com-
ponent of AHCC is oligosaccharides, which contain
-1,4 glucans and partially acetylated
-1,4 glucans with
a molecular weight of around 5000 Daltons. AHCC has
been shown to increase the number and function of den-
dritic cells in healthy adult humans [13] and enhance
both the activation and proliferation of CD4+ and CD8+ T
cells in tumor-bearing mice [14]. AHCC also strength-
ened the chemotherapeutic effects of UFT (tegafur and
uracil in a 4:1 molar concentration) for mammary ade-
nocarcinoma SST-2 cells in rats [15] and cisplatin for
Colon-26 tumor cells in mice [16]. Furthermore, two
human clinical studies in liver cancer patients showed a
significant increase in survival rate among those taking
AHCC. [17,18] Several studies have explored the allevi-
ating effects of AHCC for chemotherapy-related side
effects. In cisplatin-treated tumor-bearing mice, AHCC
improved food consumption, renal damage and myelo-
suppression [16]. The role of AHCC in attenuating vari-
ous side effects was also explored in non-tumor-bearing
mice receiving monotherapy with paclitaxel, or multi-
drug chemotherapy including cisplatin plus paclitaxel,
cisplatin plus 5-fluorouracil, 5-fluorouracil plus irinote-
can, cyclophosphamide plus doxorubicin, and 6-mercapto-
purine plus methotrexate [19,20]. In newborn rats, the
AHCC-treated group was protected from cytosine arabi-
noside-caused hair loss [20].
We investigated the influence of AHCC on some of
the side effects associated with GEM as an initial study
in preparation for a human clinical trail. Non-tumor-
bearing mice, but not tumor-bearing mice, were chosen
so that the intrinsic alterations related to the anticancer
agent could be assessed independent of oncological
variables. In the present study, we focused on GEM-in-
duced hematotoxicity including bone marrow suppres-
sion, which is a dose-limiting toxicity.
2. Materials and Methods
2.1. Reagents
Active hexose correlated compound (AHCC; Amino Up
Chemical Co., Ltd., Sapporo, Japan) was produced from
the mycelia culture of Lentinula edodes in a manufactur-
ing process according to Good Manufacturing Practice
(GMP) standards for dietary supplements, and ISO9001:
2008 and ISO22000: 2005 criteria [16]. After pre-culti-
vation in flasks, the basidiomycete was cultured in 15-ton
large tanks for 45 days, and then AHCC was obtained
through filtration, sterilization, concentration and freeze-
drying. Gemcitabine (GEM) is a commercially available
anticancer drug as Gemzar Injection (Eli Lilly Japan K.
K., Kobe, Japan), and the drug was obtained from JUN-
SEI CHEMICAL CO., LTD. (Tokyo, Japan).
2.2. Animals
Specific pathogen-free male ddY mice were purchased
from Japan SLC, Inc. (Hamamatsu, Japan) and studied at
six weeks of age. Animals were maintained in a tem-
perature- and humidity-controlled room at 23˚C ± 1˚C
and 55% - 60%, respectively, under a 12-hour light-dark
cycle (lights on 08:00 to 20:00), fed a standard pelleted
rodent chow (CE-2; CLEA Japan Inc., Tokyo, Japan),
and given water ad libitum. Mice were divided into three
groups: control (untreated), GEM alone, and GEM plus
AHCC. Each group consisted of ten mice.
2.3. Treatments
The GEM solution was injected intraperitoneally at a
dose of 400 mg/kg (1200 mg/m2) once a week for three
weeks (days 7, 14 and 21). The treatment was similar to
the regimen actually used in clinical practice (1000
mg/m2 of weekly drip infusion three times followed by
one week cessation of the drug). AHCC was prepared as
a solution at a dosage of 1 g/kg and administered daily by
gavage to mice seven days before the first injection of
GEM and throughout the experiment (day 1 to day 28).
The control group received a vehicle (saline) instead of
GEM and AHCC. All animals were killed under anesthe-
sia, and blood, bone marrow (BM) cells, spleen and kid-
ney were harvested at day 28.
Since the effect of AHCC was assessed at a dosage
range from 100 mg/kg to 1 g/kg in previous studies,
[14-16,19,20] a dose of 1 g/kg of AHCC was chosen in
the current study. The experimental protocol was ap-
proved by the Animal Care Committee of Amino Up
Chemical Co., Ltd.
2.4. Evaluation of Parameters
The following parameters were assessed: body weight,
food consumption, liver function (serum aspartate ami-
notransferase; AST), kidney function (blood nitrogen
urea; BUN), hematological toxicities (peripheral total
white blood cell count and hemoglobin content), and
myelosuppression. Body weight and food consumption
were measured twice a week. Serum AST and BUN were
assessed using Transaminase CII-test WAKO and Urea
Nitrogen B-test WAKO assay kits (Wako Pure Chemical
Industries Limited, Osaka, Japan), respectively. Cardiac
blood samples were diluted to 1:10 with Turk solution
(Wako Pure Chemical Industries Limited) to determine
Copyright © 2012 SciRes. IJCM
Active Hexose Correlated Compound (AHCC) Alleviates Gemcitabine-Induced
Hematological Toxicity in Non-Tumor-Bearing Mice 363
the number of total white blood cells in accordance with
the Nageotte chamber counting procedure, [21] and he-
moglobin content in blood was measured using a Hemo-
globin B-test kit (Wako Pure Chemical Industries Lim-
ited). Myelosuppression was determined by measuring
BM cell viability and by evaluating the responses to col-
ony forming unit granulocyte-macrophage (CFU-GM)
and burst forming unit erythroid (BFU-E).
BM cell viability was determined by collecting BM
cells from the femur, which were first suspended in
0.83% NH4Cl solution and incubated at 37˚C for ten
minutes to hemolyze red blood cells. After centrifugation,
the cells were prepared at a concentration of 1 × 107
cells/mL in DMEM supplemented with 10% FBS. A
100-L aliquot of the suspension was cultured in a
96-well plate for three days, and the viability (percent of
control group) of BM cells was estimated by a MTT as-
say. The detection of CFU-GM and BFU-E was per-
formed using a colony forming cell assay kit, MethoCult
(StemCell Technologies, Vancouver, Canada). Briefly,
BM cells were suspended in Iscove’s MDM (IMDM)
with 2% FBS and the suspension (2 × 105 cells/mL) was
mixed with methylcellulose medium containing rmSCF,
rmIL-3 and rhIL-6 (MethoCult 3534) at a 1:9 ratio. The
prepared BM cells (2 × 104 cells/mL) were plated onto a
35-mm dish and incubated at 37˚C for eight days to form
CFU-GM colony. For a mature BFU-E assay, after
IMDM with 2% FBS was added at a 1:9 ratio to methyl-
cellulose medium containing rhEpo (MethoCult 3334),
BM cells (2 × 106 cells/mL) in IMDM with 2% FBS
were mixed with the diluted methylcellulose medium at a
1:9 ratio. The prepared BM cells (2 × 105 cells/mL) were
plated onto a 35-mm dish and incubated at 37˚C for four
days. Following the individual incubation time, CFU-
GM and mature BFU-E colonies were counted under a
microscope to quantify murine hematopoietic progenitor
2.5. Reverse Transcription Polymerase Chain
Expression of granulocyte-macrophage colony-stimulating
factor (GM-CSF), erythropoietin (EPO) and beta-2-
microglobulin (B2M) mRNA was determined using a
quantitative reverse transcription polymerase chain re-
action (RT-PCR). Total RNA was extracted from 100 mg
of spleen and kidney with TRIzol reagent (Invitrogen
Corp., Carlsbad, CA, USA) according to the manufac-
turer’s protocol. First-strand cDNA was obtained by in-
cubation of 1.6 g of total RNA with PrimeScript 2 1st
strand cDNA Synthesis kit (Takara Bio Inc., Otsu, Japan),
and the RT product was then diluted to 10 g/L and
subjected to PCR using TaKaRa ExTaq (Takara Bio Inc.).
Forty cycles of amplification were carried out for GM-
CSF mRNA, and EPO mRNA and B2M mRNA were 37
and 22 cycles, respectively. The condition of each cycle
was denaturing at 94˚C for 30 seconds, annealing at 59˚C
(GM-CSF and B2M) and 65˚C (EPO) for 45 seconds,
and extension at 72˚C for 30 seconds. The primers are
described as follows; GM-CSF:
5’-GGCCTTGGAAGCATGTAGAG-3’ (sense) and 5’-
5’-CCACCCTGCTGCTTTTACTC-3’ (sense) and 5’-
5’-TAGCTGTGCTCGCGCTACT-3’ (sense) and 5’-
AGTGGGGGTGAATTCAGTGT-3’ (antisense). The gene
bands in each sample were normalized to the corre-
sponding B2M band using Alpha Innotech redTM (Alpha
Innotech Corp., San Leandro, CA, USA).
2.6. Statistical Analysis
Experimental data are shown as mean ± standard error of
the mean (SEM). Data were analyzed by one-way analy-
sis of variance (ANOVA). Fisher’s Protected Least Sig-
nificance Difference (PLSD) was used as a post hoc test,
and values of p less than 0.05 were determined to be sta-
tistically significant.
3. Results
3.1. Peripheral Hematological Toxicity
To determine whether AHCC is capable of protecting
against GEM-related hematotoxicity, peripheral total
white blood cell count and hemoglobin content in blood
were monitored. As shown in Figures 1(a) and (b), GEM
treatment was significantly associated with reductions of
leukocyte count and hemoglobin content (p < 0.01), and
supplementation with AHCC completely ameliorated
both hematological toxicities (p < 0.01). The values of
white blood cells (×106 cells/mL) in the control, GEM,
and GEM + AHCC groups were 3.05 ± 0.13, 2.01 ± 0.12,
and 3.03 ± 0.13, respectively. Hemoglobin content (g/dL)
was 14.4 ± 0.2 (control), 13.1 ± 0.3 (GEM), and 14.7 ±
0.3 (GEM plus AHCC).
3.2. Bone Marrow (BM) Suppression
To elucidate the alleviating effect of AHCC for GEM-
induced myelosuppression, BM damage was assessed by
BM cell viability and the colony forming ability of hema-
topoietic progenitor cells. The viability of BM cells iso-
lated from GEM-treated mice was lower than that of the
control group (p < 0.01; Figure 2), and AHCC admini-
stration significantly reversed the decline although it did
not achieve complete recovery (p < 0.01 vs GEM, con-
trol). Treatment with GEM alone significantly lowered
Copyright © 2012 SciRes. IJCM
Active Hexose Correlated Compound (AHCC) Alleviates Gemcitabine-Induced
Hematological Toxicity in Non-Tumor-Bearing Mice
Figure 1. Alleviating effect of AHCC for GEM-related he-
maotopoietic toxicity. Blood was collected from mice on the
final day of the experiment (day 28), and GEM-induced
hematotoxity was evaluated using two parameters, which
were peripheral total white blood cell count (a) and hemo-
globin content in blood (b). Blood samples were diluted to
1:10 with Turk solution to determine the number of total
white blood cells based on the Nageotte chamber counting
procedure. Hemoglobin content was analyzed by a Hemo-
globin B-test WAKO assay kit. The values show the mean ±
SEM. *p < 0.01 vs control, GEM plus AHCC.
Figure 2. Ameliorative effect of AHCC on bone marrow
(BM) cell viability. On day 28, BM cells were isolated from
femurs of mice with or without GEM injection, and the
hemolyzed BM cells (1 × 107 cells/mL) were cultured in a
96-well plate for 3 days. The viability (% of control group)
of BM cells was estimated by a MTT assay. The values (%
of control; mean ± SEM) in the control, GEM alone, and
GEM plus AHCC groups were 100.0 ± 1.5, 77.5 ± 1.3 and
89.0 ± 0.9, respectively. *p < 0.01 vs control, GEM plus
AHCC, **p < 0.01 vs control.
both CFU-GM and BFU-E forming abilities (p < 0.01;
Table 1), while the lowering was entirely recovered to
control level by AHCC administration.
3.3. Expression of GM-CSF and EPO mRNA
Expression of GM-CSF and EPO mRNA in spleen and
kidney, respectively, was compared among control, GEM
alone, and GEM plus AHCC groups. The expression
level was calculated as a percent of control after each
band of GM-CSF and EPO was normalized to the corre-
sponding B2M band (Table 2). The mRNA levels of
both GM-CSF and EPO in the GEM alone group were
significantly higher than those of the control and the
GEM plus AHCC groups (p < 0.05). In contrast, the ex-
pression levels in AHCC-treated mice were identical to
3.4. Other Toxicities
No changes in body weight, food consumption, and liver
and renal functions were noted at the completion of the
study. The average of body weight (g) was 35.4 ± 1.0,
36.3 ± 0.7, and 35.9 ± 0.6 in the control, GEM alone, and
GEM+AHCC groups, respectively. Serum AST and
BUN values were also normal and did not change during
the course of the study (data not shown), which was con-
sistent with previous data [10].
4. Discussion
Gemcitabine (GEM) has shown activity in a variety of
solid tumors [22]. The drug has been approved for the
treatment of non-small cell lung cancer, pancreatic can-
Table 1. Colony forming responses of CFU-GM and BFU-E.
Control 88.3 ± 1.7 119.3 ±6.1
GEM 64.3 ± 8.6* 29.0 ± 0.6**
GEM+AHCC 104.0 ± 3.0 109.0 ± 8.1
All values (colony counts) represent the mean ± SEM. *p < 0.05 vs control,
p < 0.01 vs GEM + AHCC, **p < 0.01 vs control, GEM + AHCC. CFU-GM:
colony forming unit-granulocyte macrophage, BFU-E: burst forming unit-
Table 2. mRNA levels of GM-CSF and EPO.
Control 100.0 ± 27.4 100.0 ± 6.6
GEM 323.3 ± 74.1* 161.9 ± 19.4*
GEM+AHCC 92.9 ± 20.0 99.6 ± 3.5
All values (% of control) show the mean ± SEM. *p < 0.05 vs control, GEM
+ AHCC. GM-CSF: granulocyte-macrophage colony-stimulating factor,
EPO: erythropoietin.
Copyright © 2012 SciRes. IJCM
Active Hexose Correlated Compound (AHCC) Alleviates Gemcitabine-Induced
Hematological Toxicity in Non-Tumor-Bearing Mice 365
cer and biliary tract cancer in Japan, and non-small cell
lung, pancreatic, ovarian and breast cancers in the United
States. Although GEM is generally well tolerated and has
a good toxicity profile, myelosuppression is the most
common side effect, which can limit dose and thus po-
tentially its therapeutic efficacy. This study was designed
to investigate the impact of AHCC in terms of side ef-
fects, particularly hematological toxicity attributable to
GEM injection, in non-tumor-bearing mice.
The treatment with GEM caused reduction of white
blood cell count and hemoglobin content, respectively
leading to leukopenia and anemia. Occurrence of leuko-
penia often induces infectious complications, which may
compromise treatment efficacy. Opportunistic infections
are a major cause of morbidity and mortality in cancer
patients receiving myelotoxic chemotherapy, resulting
from invasive fungal infections, particularly invasive
aspergillosis, and an increasing spread of Gram-positive
pathogens such as methicillin-resistant Staphylococcus
aureus and vancomycin-resistant enterococci [23]. In
current clinical practice, colony-stimulating factors such
as granulocyte colony-stimulating factor (G-CSF) and
granulocyte-macrophage colony-stimulating factor (GM-
CSF) are increasingly used to recover white blood cell
counts or increase dose-density [24]. In addition, hemo-
globin reduction results in anemia, which is associated
with a significant decrease in the quality of life and may
limit the applicability and efficacy of anticancer drugs
[25]. The treatment with recombinant human erythro-
poietin (rHu Epo) has been shown to improve anticancer
drug-induced anemia in rats [26], and alleviating anemia
with rHu Epo in humans has improved the quality of life
of cancer patients [27].
Although G-CSF and GM-CSF are generally safe, well
tolerated and have favorable outcomes, several reports of
serious G-CSF and GM-CSF associated side effects exist,
[28,29] including enhanced bone tumor growth by G-
CSF in mice in an osteoclast-dependent manner [30].
Treatment with rHu EPO also has risks such as the po-
tential to promote cellular proliferation and migration in
melanoma and breast cancer cells expressing the Epo
receptor [31,32]. AHCC exerted no influence on mRNA
levels of GM-CSF and EPO in our study when the
mRNA levels were measured. However, given the ame-
liorating effects of AHCC for GEM-associated BM cell
viability, AHCC might be useful to complement the
properties of G-CSF and GM-CSF as well as Epo. The
beneficial effects of AHCC on hematotoxicities caused
by other anticancer drugs, such as cisplatin, paclitaxel,
5-fluorouracil and irinotecan, have been reported [16,19],
although the mechanism of action is not yet clear.
AHCC supplementation was significantly associated
with an improvement in the levels of colony forming unit
granulocyte-macrophage (CFU-GM) and burst forming
unit erythroid (BFU-E), which were severely depressed
as a result of GEM treatment. AHCC might therefore
alleviate chemotherapy-related hematological toxicity
through protecting hematopoietic progenitor cells. This
result is consistent with other studies demonstrating that
-glucans promoted bone marrow cell viability
and protected the bone marrow stem cell colony forma-
tion unit from doxorubicin-induced hematological toxic-
ity, [33] as well as induced hematopoietic stem cell pro-
liferation and differentiation [34].
Despite the side effects, GEM may be a useful agent
for tumor immunotherapy since it possesses significant
immunomodulatory activity independent of its cytotoxic
effects as shown in murine tumor models [35]. Other
agents with potentially harsh side effects, such as cis-
platin, have also been to increase the susceptibility of
tumor cells to tumor-infiltrating lymphocytes or natural
killer cells [36]. Therefore, AHCC may offer promise
when used in conjunction with chemotherapy since
AHCC may help reduce side effects of drugs like GEM
or cisplatin and enable a full chemotherapeutic regimen
to be administered. Furthermore, the previous study de-
monstrated that AHCC enhanced chemotherapeutic ef-
fect of cisplatin in tumor-bearing mice [16], suggesting
an adjuvant action of AHCC.
The safety of AHCC in cancer patients and healthy
volunteers has been previously reported [13,17,18,37].
The current and previous studies suggest that AHCC
consumption may be safe in combination with GEM and
perhaps other chemotherapy agents that are not metabo-
lized via the CYP450 2D6 pathway [38] and clinical
studies are warranted.
The present study was conducted to assess whether
AHCC reduces GEM-induced side effects, particularly
hematological toxicity that is a dose limiting factor for
GEM, in non-tumor-bearing mice. As a consequence,
AHCC significantly ameliorated reduction of peripheral
total white blood cell count and hemoglobin content, and
further resulted in recovering CFU-GM and BFU-E
forming abilities. If these results are extended to humans,
AHCC might contribute to improved quality of life and
well-being of cancer patients undergoing chemotherapy
including GEM treatment.
5. Acknowledgements
We are deeply grateful to Dr. Robert M. Hackman, Uni-
versity of California-Davis, and Dr. Judith A. Smith,
University of Texas, MD Anderson Cancer Center, for
their suggestions and editorial comments.
[1] L. Hertel, J. S. Kroin, J. W. Misner and J. M. Tustin,
Copyright © 2012 SciRes. IJCM
Active Hexose Correlated Compound (AHCC) Alleviates Gemcitabine-Induced
Hematological Toxicity in Non-Tumor-Bearing Mice
“Synthesis of 2-Deoxy-2,2-difluoro-D-ribose and 2-De-
oxy-2,2-difluoro-D-ribofuranosyl Nucleotides,” The Jour-
nal of Organic Chemistry, Vol. 53, 1988, pp. 2406-2409.
[2] V. Gandhi, S. Mineishi, P. Huang, Y. Yang, S. Chubb, A.
J. Chapman, B. J. Nowak, L. W. Hertel and W. Plunkett,
“Difluorodeoxyguanosine: Cytotoxicity, Metabolism, and
Actions on DNA Synthesis in Human Leukemia Cells,”
Seminars in Oncology, Vol. 22, No. 4, 1995, pp. 61-67.
[3] V. Heinemann, Y. Z. Xu, S. Chubb, A. Sen, L. W. Hertel,
G. B. Grindey and W. Plunkett, “Inhibition of Ribonu-
cleotide Reduction in CCRF-CEM Cells by 2’,2’-Di-
fluorodeoxycytidine,” Molecular Pharmacology, Vol. 38,
No. 4, 1990, pp. 567-572.
[4] P. Huang, S. Chubb, L. W. Hertel, G. B. Grindey and W.
Plunkett, “Action of 2’,2’-Difluorodeoxycytidine on
DNA Synthesis,” Cancer Research, Vol. 51, No. 22,
1991, pp. 6110-6117.
[5] C. J. Campen, T. Dragovich and A. F. Baker, “Mana-
gement Strategies in Pancreatic Cancer,” American Jour-
nal of Health-System Pharmacy, Vol. 68, No. 7, 2011, pp.
573-584. doi:10.2146/ajhp100254
[6] G. Bepler, K. E. Sommers, A. Cantor, X. Li, A. Sharma,
C. Williams, A. Chiappori, E. Haura, S. Antonia, T. Tan-
vetyanon, G. Simon, C. Obasaju and L. A. Robinson,
“Clinical Efficacy and Predictive Molecular Markers of
Neoadjuvant Gemcitabine and Pemetrexed in Resectable
Non-Small Cell Lung Cancer,” Journal of Thoracic On-
cology, Vol. 3, No. 10, 2008, pp. 1112-1118.
[7] D. L. Richardson, F. J. Backes, L. G. Seamon, V. Zanag-
nolo, D. M. O’Malley, D. E. Cohn, J. M. Fowler and L. J.
Copeland, “Combination of Gemcitabine, Platinum, and
Bevacizumab for the Treatment of Recurrent Ovarian
Cancer,” Gynecologic Oncology, Vol. 111, No. 3, 2008,
pp. 461-466. doi:10.1016/j.ygyno.2008.08.011
[8] S. Moulder, N. Valkov, A. Neuger, J. Choi, J. H. Lee, S.
Minton, P. Munster, J. Gump, M. Lacevic, R. Lush and D.
Sullivan, “Phase 2 Study of Gemcitabine and Irinotecan
in Metastatic Breast Cancer with Correlatives to Deter-
mine Topoisomerase I Localization as a Predictor of Re-
sponse,” Cancer, Vol. 113, No. 10, 2008, pp. 2646-2654.
[9] J. W. Valle, H. Wasan, P. Johnson, E. Jones, L. Dixon, R.
Swindell, S. Baka, A. Maraveyas, P. Corrie, S. Falk, S.
Gollins, F. Lofts, L. Evans, T. Meyer, A. Anthoney, T.
Iveson, M. Highley, R. Osborne and J. Bridgewater,
“Gemcitabine Alone or in Combination with Cisplatin in
Patients with Advanced or Metastatic Cholangiocarcino-
mas or Other Biliary Tract Tumours: A Multicentre Ran-
domized Phase II Study—The UK ABC-01 Study,” Brit-
ish Journal of Cancer, Vol. 101, No. 4, 2009, pp. 621-
627. doi:10.1038/sj.bjc.6605211
[10] M. Tonato, A. M. Mosconi and C. Martin, “Safety Profile
of Gemcitabine,” Anti-Cancer Drugs, Vol. 6, 1995, pp.
27-32. doi:10.1097/00001813-199512006-00005
[11] P. J. Mansky and D. B. Wallerstedt, “Complementary
Medicine in Palliative Care and Cancer Symptom Man-
agement,” The Cancer Journal, Vol. 12, No. 5, 2006, pp.
425-431. doi:10.1097/00130404-200609000-00011
[12] I. Hyodo, N. Amano, K. Eguchi, M. Narabayashi, J.
Imanishi, M. Hirai, T. Nakano and S. Takashima, “Na-
tionwide Survey on Complementary and Alternative
Medicine in Cancer Patients in Japan,” Journal of Clini-
cal Oncology, Vol. 23, No. 12, 2005, pp. 2645-2654.
[13] N. Terakawa, Y. Matsui, S. Satoi, H. Yanagimoto, K.
Takahashi, T. Yamamoto, J. Yamano, S. Takai, A. H.
Kwon and Y. Kamiyama, “Immunological Effect of Ac-
tive Hexose Correlated Compound (AHCC) in Healthy
Volunteers: A Double-Blind, Placebo-Controlled Trial,”
Nutrition and Cancer, Vol. 60, No. 5, 2008, pp. 643-651.
[14] Y. Gao, D. Zhang, B. Sun, H. Fujii, K. Kosuna and Z.
Yin, “Active Hexose Correlated Compound Enhances
Tumor Surveillance through Regulating both Innate and
Adaptive Immune Responses,” Cancer Immunology, Im-
munotherapy, Vol. 55, No. 10, 2005, pp. 1258-1266.
[15] K. Matsushita, Y. Kuramitsu, Y. Ohiro, M. Obata, M.
Kobayashi, Y. Q. Li and M. Hosokawa, “Combination
Therapy of Active Hexose Correlated Compound Plus
UFT Significantly Reduces the Metastasis of Rat Mam-
mary Adenocarcinoma,” Anti-Cancer Drugs, Vol. 9, No.
4, 1998, pp. 343-350.
[16] A. Hirose, E. Sato, H. Fujii, B. Sun, H. Nishioka and O. I.
Aruoma, “The Influence of Active Hexose Correlated
Compound (AHCC) on Cisplatin-Evoked Chemothera-
peutic and Side Effects in Tumor-Bearing Mice,” Toxi-
cology and Applied Pharmacology, Vol. 222, No. 2, 2007,
pp. 152-158. doi:10.1016/j.taap.2007.03.031
[17] Y. Matsui, J. Uhara, S. Satoi, M. Kaibori, H. Yamada, H.
Kitade, A. Imamura, S. Takai, Y. Kawaguchi, A. H.
Kwon and Y. Kamiyama, “Improved Prognosis of Post-
operative Hapatocellular Carcinoma Patients When Treated
with Functional Food: A Prospective Cohort Study,”
Journal of Hepatology, Vol. 37, No. 1, 2002, pp. 78-86.
[18] S. Cowawintaweewat, S. Manoromana, H. Sriplung, T.
Khuhaprema, P. Tongtawe, P. Tapchaisri and W. Chai-
cumpa, “Prognostic Improvement of Patients with Ad-
vanced Liver Cancer after Active Hexose Correlated
Compound (AHCC) Treatment,” Asian Pacific Journal of
Allergy and Immunology, Vol. 24, No. 1, 2006, pp. 33-45.
[19] K. Shigama, A. Nakaya, K. Wakame, H. Nishioka and H.
Fujii, “Alleviating Effect of Active Hexose Correlated
Compound (AHCC) for Anticancer Drug-Induced Side
Effects in Non-Tumor-Bearing Mice,” Journal of Experi-
mental Therapeutics and Oncology, Vol. 8, No. 1, 2009,
pp. 43-51.
[20] B. Sun, K. Wakame, E. Sato, H. Nishioka, O. I. Aruoma
and H. Fujii, “The Effect of Active Hexose Correlated
Compound in Modulating Cytosine Arabinoside-Induced
Hair Loss, and 6-Mercaptopurine- and Methotrexate-In-
duced Liver Injury in Rodents,” Cancer Epidemiology,
Copyright © 2012 SciRes. IJCM
Active Hexose Correlated Compound (AHCC) Alleviates Gemcitabine-Induced
Hematological Toxicity in Non-Tumor-Bearing Mice
Copyright © 2012 SciRes. IJCM
Vol. 33, No. 3-4, 2009, pp. 293-299.
[21] M. Masse, C. Naegelen, N. Pellegrini, J. M. Segier, N.
Marpaux and F. Beaujean, “Validation of a Simple Me-
thod to Count Vary Low White Cell Concentrations in
Filtered Red Cells or Platelets,” Transfusion, Vol. 32, No.
6, 1992, pp. 565-571.
[22] L. Toschi, G. Finocchiaro, S. Bartolini, V. Gioia and F.
Cappuzzo, “Role of Gemcitabine in Cancer Therapy,”
Future Oncology, Vol. 1, No. 1, 2005, pp. 7-17.
[23] G. Maschmeyer and A. Haas, “The Epidemiology and
Treatment of Infections in Cancer Patients,” International
Journal of Antimicrobial Agents, Vol. 31, No. 3, 2008, pp.
193-197. doi:10.1016/j.ijantimicag.2007.06.014
[24] D. C. Dale, “Colony-Stimulating Factors for the Manage-
ment of Neutropenia in Cancer Patients,” Drugs, Vol. 62,
2002, pp. 1-15. doi:10.2165/00003495-200262001-00001
[25] D. Cella, D. Dobrez and J. Glaspy, “Control of Cancer-
Related Anemia with Erythropoietic Agents: A Review of
Evidence for Improved Quality of Life and Clinical Out-
comes,” Annals of Oncology, Vol. 14, 2003, pp. 511-519.
[26] T. Matsumoto, K. Endoh, K. Kamisango, K. Akamatsu, K.
Koizumi, M. Higuchi, N. Imai, H. Mitsui and T. Kawa-
guchi, “Effect of Recombinant Human Erythropoietin on
Anticancer Drug-Induced Anaemia,” British Journal of
Haematology, Vol. 75, No. 4, 1990, pp. 463-468.
[27] D. Cella, M. J. Zagari, C. Vandorons, D. D. Gagnon, H. J.
Hurtz and J. W. Nortier, “Epoetin Alfa Treatment Results
in Clinically Significant Improvements in Quality of Life
in Anemic Cancer Patients When Referenced to the Gen-
eral Population,” Journal of Clinical Oncology, Vol. 21,
No. 2, 2003, pp. 366-373.
[28] M. Merlano, M. Benasso, G. M. Numico, M. Danova, A.
Santelli, F. Ameli, F. Blengo, I. Ricci and M. Rosso,
“5-Fluorouracil Dose Intensification and Granulocyte-
Macrophage Colony-Stimulating Factor in Cisplatin-
Based Chemotherapy for Relapsed Squamous Cell Car-
cinoma of the Head and Neck: A Phase II Study,”
American Journal of Clinical Oncology, Vol. 21, No. 3,
1998, pp. 313-316.
[29] E. Azoulay, H. Attalah, A. Harf, B. Schlemmer and C.
Delclaux, “Granulocyte Colony-Stimulating Factor or
Neutrophil-Induced Pulmonary Toxicity: Myth or Rea-
lity?” Chest, Vol. 120, No. 5, 2001, pp. 1695-1701.
[30] A. C. Hirbe, O. Uluçkan, E. A. Morgan, M. C. Eagleton, J.
L. Prior, D. Piwnica-Worms, K. Trinkaus, A. Apicelli and
K. Weilbaecher, “Granulocyte Colony-Stimulating Factor
Enhances Bone Tumor Growth in Mice in an Osteo-
clast-Dependent Manner,” Blood, Vol. 109, No. 8, 2007,
pp. 3424-3431. doi:10.1182/blood-2006-09-048686
[31] P. Fu, X. Jiang and M. O. Arcasoy, “Constitutively Ac-
tive Erythropoietin Receptor Expression in Breast Cancer
Cells Promotes Cellular Proliferation and Migration
through a MAP-Kinase Dependent Pathway,” Biochemi-
cal and Biophysical Research Communications, Vol. 379,
No. 3, 2009, pp. 696-701.
[32] A. Mirmohammadsadegh, A. Marini, A. Gustrau, D.
Delia, S. Nambiar, M. Hassan and U. R. Hengge, “Role
of Erythropoietin Receptor Expression in Malignant
Melanoma,” Journal of Investigative Dermatology, Vol.
130, No. 1, 2010, pp. 201-210. doi:10.1038/jid.2009.162
[33] H. Lin, Y. H. She, B. R. Cassileth, F. Sirotnak and S.
Cunningham-Rundles, “Maitake Beta-Glucan MD-Frac-
tion Enhances Bone Marrow Colony Formation and Re-
duces Doxorubicin Toxicity in Vitro,” International Im-
munopharmacology, Vol. 4, No. 1, 2004, pp. 91-99.
[34] H. Lin, S. W. Cheung, M. Nesin, B. R. Cassileth and S.
Cunningham-Rundles, “Enhancement of Umbilical Cord
Blood Cell Hematopoiesis by Maitake Beta-Glucan Is
Mediated Granulocyte Colony-Stimulating Factor Pro-
duction,” Clinical and Vaccine Immunology, Vol. 14, No.
1, 2007, pp. 21-27. doi:10.1128/CVI.00284-06
[35] E. Suzuki, J. Sun, V. Kapoor, A. S. Jassar and S. M. Al-
belda, “Gemcitabine Has Significant Immunomodulatory
Activity in Murine Tumor Models Independent of Its Cy-
totoxic Effects,” Cancer Biology and Therapy, Vol. 6, No.
6, 2007, pp. 880-885. doi:10.4161/cbt.6.6.4090
[36] I. Matsuzaki, H. Suzuki, M. Kitamura, Y. Minamiya, H.
Kawai and J. Ogawa, “Cisplatin Induces Fas Expression
in Esophageal Cancer Cell Lines and Enhanced Cyto-
toxicity in Combination with LAK Cells,” Oncology, Vol.
59, No. 4, 2000, pp. 336-343. doi:10.1159/000012192
[37] E. L. Spierings, H. Fujii, B. Sun and T. Walshe, “A Phase
I Study of the Safety of the Nutritional Supplement, Ac-
tive Hexose Correlated Compound, AHCC, in Healthy
Volunteers,” Journal of Nutritional Science and Vitami-
nology, Vol. 53, 2007, pp. 536-539.
[38] C. M. Mach, H. Fujii, K. Wakame and J. Smith, “Evalua-
tion of Active Hexose Correlated Compound Hepatic
Metabolism and Potential for Drug Interactions with
Chemotherapy Agents,” Journal of the Society for Inte-
grative Oncology, Vol. 6, No. 3, 2008, pp. 105-109.
... The mechanism of AHCC action stimulates monocytes to promote T helper cell response and induce levels of IL-1β production that can promote cytokine (IL-17 and IFN-γ) production from CD4+ T cell lymphocytes (Lee et al., 2012). A study in mice showed that the group receiving gemcitabine 200 mg/m2 plus AHCC 1g/kg had higher white blood cells and hemoglobin than the group that received gemcitabine alone (Nakamoto et al., 2012). This was similar to a study in Japan which reported that AHCC can prevent anemia in pancreatic and biliary cancer patients who received gemcitabine. ...
... Active hexose correlated compound (AHCC) was reported as an immunostimulator for both innate and adaptive immunity with anti-tumor antibodies (Gao et al., 2006;Hirose et al., 2007). Furthermore, AHCC decreases both bone marrow suppression (Nakamoto et al., 2012) and adverse events of chemotherapy (Hirose et al., 2007) while improving QOL (Kidd, 2000) in cancer patients. The mechanisms of AHCC for enhancing the immune system have remained unclear. ...
... The presence of tumor infiltrating T cell lymphocytes correlates with progression-free and overall survival in advanced ovarian cancer patients (Hwang et al., 2012). In contrast to previous studies (Kidd, 2000;Hirose et al., 2007;Nakamoto et al., 2012), our study shows that AHCC administration cannot significantly increase CD4+ and CD8+ levels after completion of six cycles of platinum based chemotherapy. Moreover, bone marrow suppression and QOL were not significantly different between both groups. ...
Full-text available
Background Adjuvant chemotherapy is a required treatment for most patients with epithelial ovarian cancer (EOC) or peritoneal cancer. However, it has many adverse events which may affect oncologic outcomes. Active hexose correlated compound (AHCC) has been reported to be an immunoenhancer to decrease adverse events of chemotherapy. Materials and Methods Patients were randomized and allocated to receive either AHCC three grams/day (500mg/capsule) or placebo. These drugs were administrated as two capsules orally three times a day throughout six cycles of chemotherapy. The primary outcome was a change of CD4+ and CD8+ T cell lymphocytes in peripheral blood samples from baseline to completion of chemotherapy. Secondary outcomes were rate of bone marrow suppression, adverse events and quality of life (QOL) as assessed by Thai version of the Functional Assessment of Cancer Therapy-General (FACT-G). Results Study outcomes were analyzed in 28 patients, 14 patients in each group. Changes in CD4+ and CD8+ T cell lymphocytes levels were not significantly different between AHCC and placebo group; 43.5/ul (-237.5, 143.3) versus -69.5 /ul (-223.8, 165) for CD4+ level, p=0.61 and 49.5.0 /ul (-80, 153.3) versus 4.0 /ul (-173, 62.5) for CD8+ level, p=0.19. However, CD8+ levels were significantly higher in the AHCC group at the sixth cycle of chemotherapy; 392.5.0 /ul (310.8, 598) versus 259.5 /ul (170.5, 462.3), p=0.03. There was no difference in bone marrow suppression and QOL between the two groups. Adverse events in terms of nausea and vomiting significantly decreased but muscle pain significantly increased in the AHCC group. Conclusions Changes in CD4+ and CD8+ T cell lymphocytes from baseline were not significantly increased in AHCC group. However, CD8+T cell lymphocytes levels were significantly higher in the AHCC group at the sixth cycle of chemotherapy.
... AHCC has been used as an immunotherapeutic agent for cancer patients and healthy volunteers (32,33). AHCC has attenuated the side-effects of antitumor agents (34,35). AHCC is thought to enhance the chemotherapeutic efficacy. ...
Background: Active hexose-correlated compound (AHCC) is an extract of a basidiomycete mushroom that enhances the therapeutic effects and reduces the side-effects of chemotherapy. Our previous studies demonstrated that heat-shock protein 27 (HSP27) was involved in gemcitabineresistance of pancreatic cancer cells and it was downregulated by AHCC-treatment. However, how AHCC downregulated HSP27 is unknown. In the present study, we focused on two transcription factors reported to induce HSP27, heat shock factor 1 (HSF1) and high-mobility group box 1 (HMGB1) and investigated the effect of AHCC on their expression. Materials and Methods: KLM1-R cells were treated with AHCC and the protein expression of HSF1 and HMGB1 were analyzed by western blotting. Results: The protein expression of HSF1 in KLM1-R was down-regulated by AHCC treatment. On the other hand, the protein expression of HMGB1 was not reduced in KLM1-R cells after AHCC treatment. Conclusion: The possibility that AHCC down-regulated HSP27 through down-regulation of the HSF1, was herein shown.
... Likewise, some studies on animals have reported that AHCC intake is associated with reduction of adverse events during CT (25)(26)(27). Hirose et al. reported that AHCC could improve bone marrow repression caused by cisplatin with a significant difference in an animal model (27). Moreover, because the cell viability in the AHCC group was significantly much higher than the control group, they suggest that AHCC might recover immune depression induced by the tumor cells themselves as well as cisplatin. ...
Full-text available
The present study was conducted to determine whether active hexose correlated compound (AHCC), a functional food extracted from cultured basidiomycetes, possesses the potential to attenuate adverse events in unresectable pancreas ductal adenocarcinoma (PDAC) patients receiving chemotherapy. Unresectable PDAC patients receiving gemcitabine treatment (GEM) as the first-line chemotherapy were prospectively divided into 2 groups according to AHCC intake (AHCC group, n = 35) or not (control group, n = 40). The patients in the AHCC group ingested 6.0 g of AHCC for 2 mo. Hematological and nonhematological toxicity was compared between the AHCC and control groups. The C-reactive protein (CRP) elevation and albumin decline of the AHCC group were significantly suppressed as compared to the control group during the GEM administration (P = 0.0012, P = 0.0007). Patients in the AHCC group had less frequency of taste disorder caused by GEM (17% vs. 56%, P = 0.0007). Frequency of grade 3 in the modified Glasgow Prognostic Score (mGPS) during chemotherapy was found significantly less in the AHCC group (14%) than the control group (53%, P = 0.0005). AHCC intake can be effective in reducing the adverse events associated with chemotherapy and may contribute to maintaining the QOL of patients with PDAC during GEM administration.
Full-text available
We assessed the activity of gemcitabine (G) and cisplatin/gemcitabine (C/G) in patients with locally advanced (LA) or metastatic (M) (advanced) biliary cancers (ABC) for whom there is no standard chemotherapy. Patients, aged > or =18 years, with pathologically confirmed ABC, Karnofsky performance (KP) > or =60, and adequate haematological, hepatic and renal function were randomised to G 1000 mg m(-2) on D1, 8, 15 q28d (Arm A) or C 25 mg m(-2) followed by G 1000 mg m(-2) D1, 8 q21d (Arm B) for up to 6 months or disease progression. In total, 86 patients (A/B, n=44/42) were randomised between February 2002 and May 2004. Median age (64/62.5 years), KP, primary tumour site, earlier surgery, indwelling biliary stent and disease stage (LA: 25/38%) are comparable between treatment arms. Grade 3-4 toxicity included (A/B, % patients) anaemia (4.5/2.4), leukopenia (6.8/4.8), neutropenia (13.6/14.3), thrombocytopenia (9.1/11.9), lethargy (9.1/28.6), nausea/vomiting (0/7.1) and anorexia (2.3/4.8). Responses (WHO criteria, % of evaluable patients: A n=31 vs B n=36): no CRs; PR 22.6 vs 27.8%; SD 35.5 vs 47.1% for a tumour control rate (CR+PR+SD) of 58.0 vs 75.0%. The median TTP and 6-month progression-free survival (PFS) (the primary end point) were greater in the C/G arm (4.0 vs 8.0 months and 45.5 vs 57.1% in arms A and B, respectively). Both regimens seem active in ABC. C/G is associated with an improved tumour control rate, TTP and 6-month PFS. The study has been extended (ABC-02 study) and powered to determine the effect on overall survival and the quality of life.
Full-text available
Recombinant human erythropoietin (Epo) is used to prevent and treat tumor-related anemia and improve quality of life in cancer patients. Recent evidence suggested that Epo may adversely affect the survival of selected cancer patients by promoting tumor growth, inhibition of apoptosis, and induction of migration. Epo unfolds its effect on the Epo receptor (EpoR). We show--to the best of our knowledge for the first time--significantly increased EpoR expression in clinical melanoma metastases and primary melanomas in comparison with different sets of nevi by quantitative real-time reverse transcriptase-PCR, immunohistochemistry, and western blot analysis. When assessing the functionality of the EpoR-signaling pathway, recombinant human Epo led to the phosphorylation of JAK-2, signal transducers and activators of transcription 3 (STAT3), and ERK1/2 in several of the melanoma cell lines that were analyzed. Besides, Epo counteracted cisplatin-induced cell death in BLM and MV3 cells. Finally, Epo promoted cell migration of MV3 cells, whereas inhibition of the JAK/STAT and ERK1/2 pathways reduced Epo-mediated migration. In summary, we show the overexpression of functional EpoR expression in about half of the analyzed clinical melanoma metastasis specimens and show anti-apoptotic as well as pro-migratory effects of Epo, which is of importance for the treatment of anemia in advanced melanoma.
A program to synthesize fluorinated D-ribose and fluorinated nucleosides was initiated with hopes of finding compounds of potential value as anticancer and/or antiviral agents. Our approach is illustrated by a simple and stereocontrolled synthesis of 2-deoxy-2,2-difluoro-D-ribose. This was followed with the synthesis of a series of 1-(2-deoxy-2,2-difluororibofuranosyl)pyrimidine nucleosides. (R)-2,3-O-Isopropylideneglyceraldehyde was coupled with ethyl bromodifluoroacetate by using Reformatskii conditions to yield the carbon skeleton for the desired carbohydrate. Hydrolytic removal of the blocking groups with concomitant closure gave the γ-lactone 3. Reduction to the γ-lactol ultimately yielded 2-deoxy-2,2-difluoro-D-ribose (6). Functionalization of the difluoro carbohydrate with a leaving group at the anomeric position followed by displacement of the group with various pyrimidine bases yielded 1-(2-deoxy-2,2-difluororibofuranosyl)pyrimidine nucleosides.
Current first-line and adjuvant chemotherapeutic strategies for management of patients with pancreatic cancer are reviewed. Pancreatic adenocarcinoma is the 10th most prevalent cancer and the fourth most common cause of cancer deaths in the United States. More than 80% of patients with pancreatic cancer are diagnosed with locally advanced or metastatic disease and are not candidates for surgery; these patients often require multimodal treatment. The most widely used chemotherapy for such patients, as well as patients requiring adjuvant therapy after surgery, is gemcitabine or gemcitabine-based chemotherapy. All current chemotherapies for pancreatic cancer are associated with dose-limiting hematologic toxicity and other adverse effects that require ongoing monitoring and dosage adjustment to balance the benefits and risks of treatment. Pharmacists can play an important role in monitoring and providing drug information and guidance to patients and oncologists. Current investigational strategies include efforts to improve chemotherapy response rates and outcomes through modulation of cell signaling pathways and use of nanotechnology to improve drug delivery. Current management of pancreatic cancer is multifaceted, involving anticancer therapy, supportive care, and toxicity management. Standard systemic therapy with gemcitabine as a single agent or in combination with other cytotoxic agents provides modest benefits in terms of response and symptom control.
Active hexose correlated compound (AHCC) is an extract of a basidiomycete mushroom that is used as a supplement by some cancer patients undergoing chemotherapy; it is thought to enhance the therapeutic effects and reduce the side effects of select anticarcinogenic agents. AHCC has been reported to strengthen the anticancer effects of cisplatin (CDDP) and ameliorate its side effects in female BALB/cA mice inoculated with Colon-26 tumor cells. In this study, the role of AHCC in alleviating the side effects induced by several other anticancer drugs was explored in non-tumor-bearing mice receiving monotherapy with paclitaxel (TAX), or multi-drug chemotherapy with TAX plus CDDP, 5-fluorouracil (5FU) plus irinotecan, CDDP plus 5FU, or doxorubicin plus cyclophosphamide. Outcomes from the drug treatment groups with and without AHCC supplementation were compared to controls that received vehicle alone. The multi-drug treatments significantly reduced bone marrow cell viability in all groups and leukocyte count in all groups except for TAX+CDDP; these myelosuppresive effects were generally alleviated by AHCC. Hepatotoxicity and nephrotoxicity caused by the treatments that included TAX and CDDP were also significantly improved by AHCC. The death rate was 20 to 30 percent in all treatment groups except TAX+CDDP, and supplementation with AHCC greatly reduced or eliminated mortality. These results support the concept that AHCC can be beneficial for cancer patients receiving chemotherapy.
Active hexose correlated compound (AHCC) (a mixture of polysaccharides, amino acids, lipids and minerals derived from cultured mycelia of a Basidiomycete mushroom, Lentinula edodes) was used to assess amelioration of alopecia (hair loss) caused by cytosine arabinoside (Ara-C) and modulation of liver injury caused by single doses 6-mercaptopurine (6-MP) plus methotrexate (MTX). Follicular integrity and hair growth was assessed in male and female SD neonatal rats (8 days old) treated with a single dose of Ara-C (30 mg/kg/day, i.p.) and AHCC (500 mg/kg/day, p.o.) for 7 consecutive days. The side effects of a single oral dose of 6-MP (2.5mg/kg body weight) plus MTX (30 mg/kg body weight) and their amelioration by treatment with AHCC (1000 mg/kg body weight) for 28 days were assessed in male ddY mice (8 weeks old). Of the Ara-C treated rats 71.4% showed severe alopecia and 28.6% showed moderate alopecia. However, the AHCC (p.o.)-treated Ara-C group was significantly protected from alopecia. Ara-C treated rats had profound loss of hair follicles but the Ara-C plus AHCC-treated group had mild losses of follicles. AHCC supplementation to the 6-MP- and MTX-treated mice significantly increased body weight, erythrocytes, leukocytes and serum albumin, improved liver hypertrophy and degeneration, normalized the activities of serum glutamic oxaloacetic transaminase (sGOT) and serum glutamic pyruvic transaminase (sGPT), and enhanced liver drug-metabolizing enzymes. Co-administration of AHCC significantly reduced the side effects associated with Ara-C, 6-MP and MTX. However, the molecular mechanism for AHCC activity and its clinical integrity for use needs defining.
The role of erythropoietin receptor (EpoR) expression in tumor cells and the potential of EpoR-mediated signaling to contribute to cellular proliferation and invasiveness require further characterization. To determine whether EpoR expression and activation in tumor cells modulates intracellular signal transduction to promote cellular proliferation and migration, we employed a novel experimental model using human breast cancer cells engineered to stably express a constitutively active EpoR-R129C variant. EpoR-R129C expression resulted in increased cellular proliferation and migration of breast cancer cells and these effects were associated with significantly increased Epo-induced phosphorylation of ERK1/2, AKT and c-Jun-NH2-kinase (SAPK/JNK) proteins. Expression of the constitutively active EpoR-R129C receptor promoted the proliferation and migration of breast cancer cells via activation of ERK- and SAPK/JNK-dependent signaling pathways, respectively. These findings suggest that EpoR over-expression and activation in breast cancer cells has the potential to contribute to tumor progression by promoting the proliferation and invasiveness of the neoplastic cells.
Active hexose correlated compound (AHCC), a Basidiomycotina extract, is a well-tolerated nutritional supplement with no reported adverse effects. It has demonstrated potential antitumor activity and immune modulator activity. However, there is no current information regarding its metabolism and the potential for drug-drug interactions for AHCC in combination with chemotherapy. The objective of this study was to characterize AHCC hepatic metabolism, specifically involving the potential for drug interactions with selected chemotherapy agents. High-throughput cytochrome P-450 (CYP450) metabolism inhibition experiments were conducted in vitro evaluating CYP450 3A4, 2C8, 2C9, and 2D6 followed by an evaluation of AHCC as a substrate of these same isoenzymes. An ex vivo model of cryopreserved human hepatocytes was used to evaluate the CYP450 metabolism induction potential of AHCC for CYP450 3A4, 2C8/2C9, and 2D6. No inhibition of CYP450 activity was observed in presence of AHCC; however, AHCC was a substrate of CYP450 2D6. The CYP450 induction metabolism assays indicate that AHCC is an inducer of CYP450 2D6. AHCC does have the potential for drug-drug interactions involving CYP450 2D6, such as doxorubicin or ondansetron; however, the overall data suggest that AHCC would be safe to administer with most other chemotherapy agents that are not metabolized via the CYP450 2D6 pathway.
To describe the response rate (RR), progression-free survival (PFS), and toxicity profile of combination gemcitabine, platinum, and bevacizumab (GPB) for the treatment of recurrent epithelial ovarian cancer (EOC). A chart review of all patients with recurrent EOC who were treated with D1, D15 GPB in a 28-day cycle at a single institution was performed. Standard doses were gemcitabine 1000 mg/m(2), cisplatin 30 mg/m(2) or carboplatin AUC 3, and bevacizumab 10 mg/kg. All patients were analyzed for toxicity. RR and PFS were assessed in all patients who received at least 2 cycles of GPB. Thirty-five patients were identified, and 33 received at least 2 cycles of GPB. The majority of patients (80%) were platinum sensitive. Patients received a median of 6 cycles of GPB (range 1-24). Sixteen patients (48%) had a complete response (CR), and 10 patients (30%) had a partial response (PR), for a total RR of 78%. An additional 5 patients (15%) had stable disease, and only 2 (6%) patients had progressive disease. The median overall PFS was 12 months (95% CI 7-15), with a median follow-up time of 10 months (2-22). Two patients (6%) had bowel perforations, and both survived. Hematologic toxicities were most common, with 29% and 14% of patients experiencing grade 3 or 4 neutropenia and thrombocytopenia respectively. The combination of GPB demonstrated excellent efficacy for the treatment of recurrent EOC. However, serious toxicities occurred, and the safety profile of this combination requires further study.
A trial of neoadjuvant gemcitabine and pemetrexed (GP) chemotherapy in patients with resectable non-small cell lung cancer was conducted. The goal was to achieve a disease response rate of 50% and to determine if the expression levels of genes associated with GP metabolism are predictive of response. Patients had staging with a computed tomography scan, whole body F-18 fluorodeoxyglucose positron emission tomography, and mediastinoscopy. Four biweekly cycles of GP were given. Patients were restaged, and those with resectable stage IB-III disease had thoracotomy. Fresh frozen tumor specimens were collected before and after chemotherapy and the mRNA levels of 14 target genes determined by real-time reverse transcription polymerase chain reaction. Fifty-two patients started therapy. The radiographic disease response rate was 35% (95% confidence interval 21.7-49.6%), and the progression rate was 6%. Forty-six patients had a thoracotomy. The complete tumor resection rate was 77% (40/52). There were no perioperative deaths or deaths related to chemotherapy. Tumor response to chemotherapy was inversely correlated with the level of expression of RRM1 (p < 0.001; regulatory subunit of ribonucleotide reductase) and TS (p = 0.006; thymidylate synthase); i.e., the reduction in tumor size was greater in those with low levels of expression. Neoadjuvant GP is well tolerated and produces an objective response rate of 35%. Tumoral RRM1 and TS mRNA levels are predictive of disease response and should be considered as parameters for treatment selection in future trials with this regimen.