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high protein diet. These findings were consistent
with the results of our dietary studies discussed in
a later section.
Dr. Lijinsky, and his colleagues compared the
carcinogenic effectiveness of BHP, BOP, HPOP
and NDMM in SGH and found that, based on the
relatively low levels of administered carcinogen,
BOP appeared to be the most potent carcinogen
for the pancreas 171 . HPOP was next in potency
but was considerably weaker than BOP. NDMM,
which was similar in potency to HPOP, did not
induce a significant incidence of liver tumors. BHP
was considerably less potent than the other three
compounds. These results did not support the
opinion that HPOP is the proximate carcinogenic
metabolite of all three compounds in the SGH but
instead suggested that these compounds might
have acted through the formation of different
unknown carcinogenic metabolites.
Carcinogenicity of MeNDMM, its cis and trans
isomers and the effect of deuterium labeling were
investigated in SGH 172 . The cis isomer was more
potent in inducing tumors of the liver and
pancreas than the trans isomer. The beta
deuterium labeled compound was less
carcinogenic and the alpha deuterium labeled
compound was more carcinogenic than the
unlabeled material. There was no significant
difference between the isomers in activation to a
bacterial mutagen by pancreas microsomes or in
binding to DNA of the pancreas.
Although it is a potent pancreatic carcinogen,
MeNDMM lacked selectivity for the pancreas. In
search of a more effective and specific pancreatic
carcinogen with cyclic structures, Raha from the
Eppley Institute synthesized N-nitrosobis(2oxobutyl)amine
(BOB) and N-nitroso(2oxobutyl)(2-oxopropyl)amine
(OBOP) (Fig. 42)
and used them in SGH by subcutaneous
injection 173 . Interestingly, both compounds, like
MeNDMM, showed a cytotoxic effect on
pancreatic islets in high doses, comparable to the
effect of alloxan and streptozotocin. In lower
doses, OBOP had a greater ductal carcinogenic
effect (up to 100%) than BOB (6% to 78%
42
depending on the dose), the primary target of
which was the liver. OBOP but not BOB induced
renal tumors (20% to 80%). Hence, factors other
than cyclization, such as the presence of the 2oxo
groups in the β-position of the molecule
appear to be important for pancreatic
carcinogenicity of this class of nitrosamines. It
was noteworthy that both BOB and OBOP caused
hyperplasia of the urinary tract epithelium and
OBOP, in addition, produced urethral papilloma.
The affinity to the urethral epithelium appears to
be related to the butyl-group in these two
carcinogens.
Although other nitroso compounds were shown to
induce pancreatic neoplasms in SGH 160, 174 , their
effect was not as specific for the pancreas as that
of BOP. This may be a link in elucidating the
etiology of pancreatic cancer in animals and,
hopefully, also in man. These nitrosamines
included N-nitrosovinyl-ethylamine, N -nitroso(1acetoxypropyl)
propylamine, and N- nitrosopropyl-
propionamide, which, when given subcutaneously
weekly for life, induced pancreatic ductular
adenomas (but no adenocarcinornas) in 77%,
40%, and 17% of the hamsters, respectively 175-177 .
Figure 43. shows the structural relationship
between the molecular structure of the selected
nitrosamines and the their pancreatic
carcinogenic potency. It indicates that
carboxylation in the β-position plays an important
role.
Figure 43. Relationship between the molecular
structure of nitrosamines and their carcinogenic
potency for the pancreas.