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МЕДИЦИНСКИ ПРЕГЛЕД, 2024, 60 (4)
11
1Onkoderma – Clinic for Dermatology, Venereology and Dermatologic Surgery
2Department of Dermatology and Venereology, Medical Initute of Miniry of Interior – Soa
221
1Онкодерма – Клиника по дерматология, венерология и дерматологична хирургия
2Катедра по дерматология и венерология, Медицински институт на МВР – София
The association of nitrosogenesis with skin cancer, and in particular with keratino-
cytic forms of skin cancer, is primarily or mainly determined by the activation of
carcinogenesis and/or mutagenesis. The mutagenic and carcinogenic potential
of nitrosamines/NDSRIs identified as contaminants in drugs worldwide varies
considerably. Data for some of their representatives are scarce (and sometimes)
to completely lacking as official data. The pharmaco-oncogenesis of skin cancer
is mainly due to the presence of nitrosamines in the drugs, although the latter are
not defined and labelled even as an availability. The overlap of the mutant genes
(RAS/p53) in patients with basal cell carcinomas with those induced by some
of the nitrosamines/NDSRIs identified in the drugs (again p53/RAS) are also
further evidence of their potential mutagenic/carcinogenic action in humans. We
present a 92-year-old patient who developed a short-term basal cell carcinoma
under the right lower eyelid, treated successfully surgically by island flap, as
part of polymedication with tamsulosin and perindopril. We analyze the potential
role of nitroso-tamsulosin and nitroso-perindopril in the context of nitrosogen-
esis/pharmaco-oncogenesis concerning skin cancer. Elimination regimens for
nitrosamines/NDSRIs in drugs worldwide should be more than strictly mandatory
because their short-term intake in the context of polymedication polycontamina-
tion could lead to the development of keratinocytic cancer, analogously to the
case we presented next. Even more disturbing are the latest scientific data that
alarm about certain nitrosamines that are also strong photocarcinogens.
mutagens, carcinogens, skin cancer, island flap, nitrosogenesis, mutagenesis, car-
cinogenesis, nitroso-perindopril, nitroso-tamsulosin
Address for correspondence: Prof. Georgi Tchernev, MD, e-mail: georgi_tchernev@yahoo.de,
рhone: +359 885 588 424
Връзката на нитрозогенезата с рака на кожата, и по-специално с кератиноцит-
ните форми на рак на кожата, се определя главно или основно от активира-
нето на карциногенезата и/или мутагенезата. Мутагенният и канцерогенният
потенциал на нитрозамини/NDSRI, идентифицирани като замърсители в ле-
карствата в световен мащаб, варира значително. Данните за някои от техните
представители са оскъдни, а понякога – напълно липсващи като официални
данни. Фармакоонкогенезата на рака на кожата се дължи главно на наличието
G. Tchernev, I. Todorov, L. Ivanov, S. Kordeva.
Basal cell carcinoma development after combined administration...
в лекарствата на нитрозамини, въпреки че не са дефинирани и етикетирани
дори като наличност. Припокриването на мутиралите гени (RAS/p53) при паци-
енти с базоцелуларни карциноми с тези, предизвикани от някои от нитрозами-
ните/NDSRI, идентифицирани в разнороден тип лекарства (отново p53/RAS),
представляват на практика допълнително доказателство за потенциалното им
мутагенно/канцерогенно действие при хората. Представяме 92-годишен паци-
ент, който е развил краткосрочно (в рамките на полимедикация с тамсулозин и
периндоприл) базоцелуларен карцином под долния десен клепач, лекуван ус-
пешно хирургично чрез островна пластика. Анализираме потенциалната роля
на нитрозо-тамсулозин и нитрозо-периндоприл в контекста на нитрозогенезата/
фармакоонкогенезата по отношение на рака на кожата. Още по-обезпокоител-
ни са последни научни данни, които алармират за наличие на някои нитрозами-
ни, които са на практика и силни фотоканцерогени.
мутагени, канцерогени, рак на кожата, островна пластика, нитрозогенеза,
мутагенеза, карциногенеза, нитрозо-периндоприл, нитрозо-тамсулозин
Aдрес за кореспонденция: Проф. д-р Георги Чернев, e-mail: georgi_tchernev@yahoo.de, тел.: +0 885 588 424
I
The concepts of pharmaco-oncogenesis/onco-
pharmacogenesis and pharmacologically determi-
ned/defined mutagenesis of skin cancer are com-
pletely new findings, which, unfortunately, are not just
a myth but reality. It should not be surprising given the
polycontamination of over 300 drugs worldwide with
nitrosamine/NDSRIs.
Various research groups worldwide have linked
the intake of ACE inhibitors to the development of
keratinocytic cancers [1, 2]. What is “remarkable”
about these works is that they do not thematize the
role of the nitroso component in relation to skin can-
cer, but generally focus their attention to phototoxicity
and its generally accepted and still leading pathoge-
netic role in relation to cutaneous carcinogenesis [1,
2]. Circumstances such as comorbidity, nitrosamine
contamination and polymedication also remain com-
pletely unnoticed in the aforementioned works.
More recent follow-ups of patients taking hetero-
geneous ACE inhibitors who subsequently developed
keratinocytic cancers have linked this clinical mani-
festation rather to the nitrosamines present in the
drugs [3-5].
A patient who developed a keratinocytic tumor
near the eye is presented, and the possible carcino-
genic/mutagenic role within the combined intake of
nitroso-tamsulosin and nitroso-perindopril, as well as
the significance of tests, which prove or disprove the
respective aforementioned (carcinogenic/mutagenic)
activity, are discussed.
A 92-year-old male presented to the dermatol-
ogy department with primary complaints of lesions
located on both lower eyelids that have been present
for approximately 3-4 years (figs 1a/2a). These tumor
formations, measuring around 0.4-0.5 cm in diame-
ter, have shown gradual progression over time.
The patient underwent a transurethral resection in
November 2023 for prostatic hyperplasia and bladder
stones. He has been managing arterial hypertension
with perindopril arginine 10 mg administered once in
the evening for the past 5 years.
Therapy with tamsulosin 0.4 mg once daily was
given for 8 years.
The patient denied having any allergies or fam-
ily history of skin malignancies. No history of painful
sunburns was reported.
He presented with a request for physical evalua-
tion of the lesions and further therapeutic approach to
be established.
The dermatological examination revealed in the
area of the left lower eyelid, a pronounced lesion
covered with a crust, measuring approximately 0.3
cm in diameter; and in the area of the right lower eye-
lid, a nodular tumor-like formation with a pearl-like
edge and superficial telеangiectasias, with ulcera-
tion at one end (fig. 1a). The lesion was suspected
for basal cell carcinoma (BCC). Lymph nodes were
not palpable.
A lesion similar in morphology is seen under the
right eyelid.
МЕДИЦИНСКИ ПРЕГЛЕД, 2024, 60 (4)
Routine blood tests were performed, showing no
abnormalities. The patient was recommended sur-
gery for the suspected lesions.
The lesion located on the right lower eyelid was
removed under local anesthesia with lidocaine 1%,
with an oval excision (fig. 1b). The residual defect
was managed through the implementation of an is-
land flap (fig. 1c), employing single interrupted su-
tures for precise anatomical closure (fig. 1d). Histo-
pathological verification indicated an infiltrative basal
cell carcinoma staged as T1N0M0. The postoperative
period went without any complications. The second
lesion was removed following elliptical excision as
histopathological verification was indicative of a viral
wart, with clean resection lines (fig. 2b/2c).
Clinicians are increasingly faced with the dilem-
ma: “Are normal or peak concentrations of nitrosa-
mines as contaminants in a heterogeneous class of
drugs responsible for the clinical manifestation of skin
cancer, but not only?”. Another dilemma is related to
the polymedication in the context of potential or actual
contamination with nitrosamines/NDSRIs in polymor-
bid patients, the possibility of potentiating mutagen-
esis, and subsequently of the carcinogenesis.
Differentiating or grading the significance of pho-
tocarcinogenesis from nitrosogenesis with respect to
skin cancer carcinogenesis, in practice, proves to be
a less straightforward task. But the initial parameters
for the ˝start of this event˝ seem to be definitively set.
The 2023 FDA list for the cataloguing of potential
carcinogens in medicines remains the first and cur-
rently most important starting point for addressing
this issue [6]. The FDA remains the pioneer within this
initial, global, cathartic process.
The networks of mutagenesis and carcinogenesis
are intertwined, and the consequent clinical relevance
sometimes proves difficult to unravel.
The most recent evidence in the world literature
shares the view that the nitroso component in ramip-
iril, for example, is unable to induce point mutations
under experimental/test conditions in the Nitrosation
Assay Procedure [7]. Although this one-sided and
hastily shared information should bring clarity and act
reassuring to others, its careful analysis indicates that
the absence of mutations should not be reassuring
and the reasons for this are many. Mutations are not
an equivalent, but a prerequisite for the development
of cancer, and an optional one at that.
The lack of complete correspondence/reciproc-
ity between the concepts of carcinogenicity and mu-
tagenicity in nitrosamines has been hinted at since
more than 40 years ago [8].
Nitrosamines are globally recognized carcino-
gens which in practice defines them by definition as
substances after whose intake cancer development
is registered/observed [9]. However, practically not all
carcinogens are also mutagens [9]. The definition of
a carcinogen does not require that the substance in
question gives a positive mutagenic test on prokary-
otes and that this is taken as a guarantee or credibility
of carcinogenic potential.
Nitrosamines have for years been recognized as
carcinogens that possess potent genotoxicity, carci-
nogenic activity, and in practice many of them turn out
to be mutagenic carcinogens at the same time [10].
This is what makes much of the testing defining the
G. Tchernev, I. Todorov, L. Ivanov, S. Kordeva.
Basal cell carcinoma development after combined administration...
51
concept of carcinogenicity/mutagenicity somewhat
controversial. Although these terms are used ubiqui-
tously with little thought put into their definition.
Mutagenic action is not always equivalent to car-
cinogenic action [11]. Mutagenicity is measured by
the so-called test of Ames/modified test of Ames:
tests to identify gene modifications after contact with
certain or possible carcinogens/mutagens [12, 13].
The limiting point of this type of test is that the Ames
test could, for example, miss or give negative results
against serious carcinogens (in animals) such as di-
oxin, for example [14]. That is – not all carcinogens
are mutagens and they (meaning carcinogens) may
not be ˝captured˝ by the Ames test.
On the other hand, the Ames test is based on
a bacterial system, which in practice is also not a
perfect model for the assessment of cancer in an-
imals and humans, since in bacteria (used in the
Ames test), cells are prokaryotic or unicellular/pre-
nuclear, whereas in eukaryotic organisms (animals,
plants and fungi) cells are mostly multicellular or
necessarily possess a nucleus [15]. What is left
for clinical relevance in humans? Is susceptibility
to mutation the same in differently arranged organ-
isms? It remains incompletely clear even though we
are in the 21st century, the century of innovation
and ˝universal globalization˝...
Weak mutagens can also be frequently report-
ed as negative results in the Ames test while being
strong carcinogens against multicellular organisms/
eukaryotes [15]. On the other hand, the registra-
tion of mutagenic activity, even with the Ames test,
should not define a substance as necessarily car-
cinogenic or cancer-causing. Mutations are not
equivalent to cancer. However, their absence does
not imply the absence of development of possible
future carcinogenic potential. The mutagenic com-
ponent is a good prerequisite for the development
of carcinogenic potential.
Methodologies for determining mutagenic and
carcinogenic potential in nitrosamines show differ-
ences or lack of complete reciprocity between the so-
called carcinogenic and mutagenic potential [16, 17].
Even more worrisome is the fact that certain ni-
trosoderivatives, such as nitroso-propranolol, for ex-
ample, could show negative results in the Ames test,
while at the same time these results could be positive
within assays to demonstrate gene toxicity such as
various in vitro assays [18].
That is, the Ames test is not indicative of geno-
toxicity, which excludes the induction of mutations,
but still has a strong carcinogenic effect. Or it is a
clinically significant carcinogenic effect that remains
undetected by the Ames test.
It is this type of assays (in vitro assays or in vivo
assays in rodents), which could prove to be recipro-
cal in terms of clinicopathological correlations arising
within the potentially contaminated drug intake [3-5].
Relative to the publication with nitroso-ramipril [7]
using as substrate Salmonella typhimurium (strains
TA98 and TA100 with and without metabolic activa-
tion), the negative mutagenic test (in unicellular/
bacteria organisms without organelles and nucleus),
could be defined as nonspecific and partially (why not
completely) invalid for multi-cellular organisms or hu-
mans, especially within the case we shared: intake of
actual nitrosamine-contaminated ACE inhibitors and
subsequent sequential development of skin cancer,
for example, analogous to the case of others. In this
case, the case report is similar to other cases in the
world literature [3-5].
But this negativity does not exclude a real carci-
nogenic potential, analogous to the observations with
nitroso-propranolol [18]. Without the availability of
carcinogenicity and mutagenicity tests, the substanc-
es in question could safely be classified as human
carcinogens – and this only on the basis of clinico-
pathologic correlations associated with skin cancer.
The application of 1) the CPCA assay (Carcino-
genic Potency Categorization Approach) and 2) an
improved Ames test from EMA for the identification of
nitrosamines and NDSRIs, provide some hope for a
more accurate classification of the carcinogenic and/
or (?) mutagenic potency of the compounds shared
above [19], although these identification approaches
may also be defined by the critical academic commu-
nity as also controversial.
The truth is born within the framework of con-
structive criticism, and the latter remains at present
the only guarantor of the credibility of analyses.
There are two main problems that prevent the truth
from crystallizing: 1) the unwillingness of regulators
and manufacturers to officially declare whether con-
tamination is present in drug packaging and in what
concentration, and 2) the lack of an official statement
or explanation of how it can be possible that pure pro-
duction (without nitrosamines) is present in certain
geographical regions and not in others.
In vivo testing in rodents is perceived by many
analysts as a much more serious proof of the pres-
ence of a relevant carcinogenic potential.
The Nitrosogenesis of skin cancer could be re-
lated to 1) mutagenesis, 2) carcinogenesis, or 3)
both of these simultaneously. In certain cases, these
МЕДИЦИНСКИ ПРЕГЛЕД, 2024, 60 (4)
two concepts (carcinogenesis and mutagenesis) are
overlapping.
In addition to the problematic issue of the prop-
erties of nitrosamines to be mutagenic or carcino-
genic, there is a currently unresolved issue of inter-
pretation of the results of testing these compounds:
there is a strong possibility that the carcinogenic
potency of nitrosamines will be compromised even
after some of the tests proposed by the regulators
have been performed. What is the solution?
The clinicopathological correlations after intake
of nitrosamine-contaminated medications also be-
come one of the most serious pieces of evidence
concerning the carcinogenic potential of the nitroso-
preparation in question.
Carcinogens in medicines do not always cause
mutations, but probably – more and more often –
skin cancer.
The definition of a carcinogen does not gener-
ally require that mutations are present after contact
with it. The definition of ‚carcinogen‘ requires, as the
only condition, that its intake is associated with an
increased incidence of a particular form of cancer
afterwards.
The lack of information on the exact concentra-
tion of a particular nitrosamine in a batch of lisinopril,
for example, does not exclude the concentration of
that ingredient from varying and/or: 1) have a direct
carcinogenic effect, to 2) have a cumulative effect
within a prolonged permanent intake, thus causing
mutations at a later stage and a subsequent/future
carcinogenic effect, or 3) have a mutagenic effect
without a phenotypic manifestation in terms of can-
cer generation/carcinogenic effect.
Of interest are 1) the relatively low carcinogenic
potency of lisinopril according to the 2023 FDA rec-
ommendations for allowable carcinogen availability in
drugs [6]: such of 5, and 2) the relatively short-term
occurrence of skin cancer after initiation of this medi-
cation. It is these details that require further analy-
sis of the data available to date, but also future data,
concerning not only 1) the intake of a carcinogen/s,
2) the determination of its concentration (does the
increased concentration of nitrosamines in drugs
compensate for their lower carcinogenic potency?)
and also 3) genetic analysis of tumour tissue from a
significant number of real patients (and analysis for
which nitrosamine is there and if there is a reciprocity
between mutagenic and carcinogenic potency?).
An analogous and currently unresolved problem
is that of polycontamination of polymedication and
the subsequent development of skin cancer [3-5].
The patient we described had been taking 2 poten-
tially nitrosamine-contaminated drugs: tamsulosin 0.4
mg for 8 years and perindopril 10 mg for 5 years. The
tumor under the eye first appeared, according to the
anamnestic data, about 3 years ago or 2 years after
combined intake of perindopril and tamsulosin. The
lack of accurate indication on the packaging of the
preparations as to whether they contain nitrosamines
and in what concentrations remains concerning to
say the least.
Polycontamination within polymedication could
also be seen as highly problematic. Perindopril
has a carcinogenic potency of 5, and tamsulosin
a carcinogenic potency of 4 according to the 2023
FDA list [6].
Combined intake of NDSRIs within polymedica-
tion (perindopril/ tamsulosin) and polymorbidity, could
be risky in the short term in terms of keratinocyte can-
cer development. There is currently no literature data
on the cumulative intake of NDSRIs and potentiation
of mutagenesis/carcinogenesis.
Some of the nitrosamines are considered to be
mutagens that induce mutations specifically in the p53
genome regulator and the RAS oncogenes [20, 21].
The so-called genome regulator, p53, has been
known for decades in humans as a key mutant
gene in all forms of skin cancer: keratinocytic and
melanoma [22-27].
The situation in humans is analogous to the in-
duction of RAS mutations in patients with keratino-
cytic tumors [28, 29] and cutaneous melanoma [30].
It is undisputed that whether nitrosamines/
NDSRIs are 1) mutagens, 2) carcinogens, 3) non-
carcinogens or 4) mutagens with subsequent carci-
nogenic effects, their presence within the drug intake
should be eliminated and not only adequately con-
trolled. Reason for that is that they can cause cancer,
skin cancer. And that’s enough.
Two recently published papers have shed con-
siderable light on the issues concerning skin cancer
related nitrosogenesis and oncopharmacogenesis:
1) Certain nitrosamines turn out to be photocar-
cinogens or substances that are able to exert their
genotoxic action only after exposure to solar radiation
with UVA [31]. However, there is a lack of testing on
the genotoxicity of nitrosamines available in pharma-
ceutical preparations. There is also a lack of any offi-
cial information on the type of nitrosamines contained
(in general) in the drugs on the market, which makes
it difficult to test their toxicity to human DNA in a tar-
geted manner.
2) The unraveling of the second dilemma con-
cerns precisely the mutagenicity of nitrosamines in
human DNA or their impact on humans-a topic that
G. Tchernev, I. Todorov, L. Ivanov, S. Kordeva.
Basal cell carcinoma development after combined administration...
has been debated for decades but has not yet found
a definitive solution. A recently published paper
proves and establishes once again the genotoxic/
mutagenic action of tobacco-specific nitrosamines
on human DNA [32].
What is surprising about the fact that the pres-
ence of similar nitrosamines/NDSRIs in drugs could
predispose to the development of cancer remains
unclear? Moreover, the genotoxicity of certain ni-
trosamines affect the so-called regulators of the ge-
nome – p53 and RAS oncogenes, or genes consid-
ered to be mainly affected in the generation of skin
cancer [33, 34, 35].
A further dilemma remains: “Are a number of ni-
trosamines (of various types) contained in different
types of drugs potent photocarcinogens?”. It is a the-
sis whose significance and plausibility could only be
proven or completely disproved once the type and
concentration of each nitrosamine/nitroso derivative
is formalized on the drug package insert.
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contamination in the calcium channel blockers (amlodipine),
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Received February 8 2024
