Download PDF - The Pancreapedia

Lesions were also found in the perineum, rectum
and external urethral ostium of females as
possible leakage of the carcinogens applied into
the vagina. In addition, tumors in the internal
tissues were also developed. BHP and BAPtreated
hamsters developed fore-stomach
papillomas in 40% and 10%, nasal cavity
papillomas and carcinomas in 90% and 90%,
laryngeal polyps in 30% and 40%, lungs
adenomas or carcinomas in 70% and 70%, liver
tumors in 40% and 90%, and pancreatic
adenomas or carcinomas in 100% and 70%,
respectively. It appeared that topically applied
BHP and BAP act locally and, due to their
absorption through the skin, also induced tumors
in internal tissues. BOP and HPOP at low doses,
however, failed to induce any epidermal
lesions 161 . Weekly application of equitoxic doses
of BOP (10 and 100 mg/kg) and HPOP (38 and
380 mg/kg) to the lip and vagina of hamsters
induced lip and vagina tumors in up to 100% with
BOP and 60% with HPOP 163-165 . Tumors were
also found in the fore-stomach, rectum, kidneys,
gall bladder, liver and nasal cavity. Skin
absorption studies demonstrated that BHP, but
not BOP is rapidly absorbed and was detectable
in blood as early as 15 minutes after its
application 165 . The results explained the reason
for BHP but not BOP or HPOP to induce
pancreatic tumors (between 36% and 86% at a
dose of 2mg and 50 mg per week, respectively)
when applied to the skin.
The induction of lip tumors in hamsters treated
topically with BOP, suggested that BOP, or its
metabolite, is excreted via saliva. In a
confirmation study, hamsters were treated with 20
or 100 mg/kg BOP plus pilocarpin at a dose of 15
mg/kg. Saliva was collected for a total of three
hours and analyzed for the presence of BOP and
other metabolites. Both BOP and HPOP were
present in approximately an equivalent amount in
the hamster’s saliva receiving the low dose, but
the amount of saliva HPOP was twice that of BOP
in hamsters treated with the high dose. The
results lend support to our notion that excreted
BOP and HPOP are responsible for lip tumors
40
following their metabolism in the epidermal tissue.
In a lower dose, the carcinogens affected the lip,
but in higher doses, the absorbed compounds
affected the internal tissues as well.
Based on metabolic studies, mentioned in detail in
the next section, N-nitrosomethyl(2oxopropyl)amine
(MOP) was found to be the
proximate metabolite of BOP, BHP, and HPOP
(Fig. 42). When given as a single dose, it induced
pancreatic ductular adenomas and carcinomas in
80% and in higher doses up to 93% of
hamsters 166 . Hence, MOP appeared to have a
greater pancreatic carcinogenic effect than
previously tested compounds, although like BOP,
it also induced neoplasm in the liver and kidneys
and in contrast to BOP, it induced nasal cavity
tumors in up to 100% of the hamsters.
Since metabolic studies in our laboratories and
elsewhere suggested that HPOP is a metabolite
of BHP, BOP and NDMM, and its carcinogenic
action is due to its ability to cyclize, we
synthesized N-nitroso-2-methoxy-2,6dimethylmorpholine
(MeNDMM) a cyclic derivative
of HPOP (Fig. 42). This compound induced,
depending on the dose levels, a 40% to 100% of
pancreatic ductular adenomas and a few
adenocarcinomas with metastases to regional
lymph nodes 167 . As with BOP, tumors were also
found in the fore-stomach, gall bladder, liver,
kidneys and vagina. Our assumption that
MeNDMM would retain its cyclic form in vivo, was
found not to be true, since hamsters metabolized
the MeNDMM to HPOP and BHP 168 . Remarkably,
however, MeNDMM showed a cytotoxic effect on
pancreatic endocrine tissue and similar to the
effect of streptozotocin it induced several mixed
endocrine-exocrine tumors and islet cell
adenomas. Hence, its effect was similar to but
weaker than streptozotocin, a cyclic nitrosourea
derivative with a known diabetogenic effect. It has
been postulated that the cyclic structure of the
streptozotocin, the glucose moiety of which
resembling the hexose sugars, facilitate their
uptake by the islet cells. In that case, the affinity
of MeNDMM to islet cells could be due to its
sugar-like molecule. Nevertheless, the results