Studies with oxidized derivatives of
N-nitrosodi-n-propylamine suggested a structure-activity relationship between
pancreatic cancer induction in Syrian hamsters and position and degree of
nitrosamine oxidation. To elucidate the importance of the position of the oxidized substituent relative to the N-nitroso group in pancreatic
carcinogenesis, we compared the toxicity and carcinogenicity of two substituted methylbutylnitrosamines.
N-Nitrosomethyl(2-oxobutyl)amine (M-2-OB) and
N-nitrosomethyl(3-oxobutyl)amine (M-3-OB) were given in equitoxic doses to male and female Syrian hamsters. The 50% lethal doses for
M-2-OB and
M-3-OB in males and females, respectively, were 92 and 160 and 705 and 810 mg/kg
body weight.
M-2-OB, although given in significantly smaller doses (minimum dose, 2.3 mg/kg
body weight) than was
M-3-OB (minimum dose, 17.6 mg/kg
body weight), induced a much broader spectrum of
neoplasms (in 17 tissues), whereas
M-3-OB induced
tumors in only 5 tissues and had no carcinogenic effect in the pancreas.
M-2-OB, however, produced pancreatic ductular-ductal
adenocarcinomas in over 90% of the males and 67% of the females, even at the lowest doses (2.3 and 4.0 mg/kg, respectively). Although both compounds caused a similar incidence of morphologically equivalent
neoplasms (mostly
adenocarcinomas) in the nasal and paranasal cavities, the remaining distribution of affected tissues differed significantly.
M-2-OB predominantly affected the lip (
epitheliomas,
squamous cell carcinomas), liver (
cholangiomas and
cholangiocarcinomas), and flank organ (
epitheliomas,
squamous cell carcinomas). The principal target organs for
M-3-OB were the cheek pouch (
papillomas, squamous cell carcinomas) and trachea (
polyps). In contrast to
M-2-OB,
M-3-OB did not induce renal and urethral
tumors. These findings indicate the importance of the 2-oxo group as a prerequisite for the carcinogenicity of methylalkylnitrosamines in the hamster pancreas; however, a methyl group in one aliphatic chain, alpha to the N-nitroso function, appears to cause the molecule to lose its selectivity for the pancreas.