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Figure 39. The molecular structure of hamster pancreatic carcinogens.
shorter latencies (41 to 52 weeks) than those in
untreated hamsters (90 to 111 weeks) 77, 80 . Since
neither DPN nor MPN affected the pancreas
similarly, it was thought that substituted aliphatic
chains in the β position are essential in the affinity
for the pancreas. This assumption was
substantiated by using
N-nitrosobis(2-hydroxypropyl)amine (BHP) (Fig.
39). After weekly subcutaneous injections of this
compound at concentrations of 500, 250, or 125
mg/kg body wt, a 100% pancreatic tumor
incidence was obtained as early as 15 weeks
after initiation of the treatment 148-152 . Grossly
visible tumors were present in 51% of the cases
measuring up to 20 mm in diameter. These
cancers had invaded the surrounding tissues and
metastasized into the lung and liver. Like the
parent compounds, DPN and MPN, BHP also
induced respiratory tract tumors. Unlike the parent
compound, BHP also produced liver tumors
(hemangioendothelioma, angiosarcoma,
cholangioma and carcinoma) as well as
adenomas and adenocarcinomas of the kidney.
36
The results of these studies highlighted the
existence of a relationship between the chemical
structure of the nitrosamine and the target tissue.
BHP not only preserved the carcinogenicity of the
DPN in the respiratory tract, but also due to its β
oxidation, primarily targeted the pancreas as well
as the liver and kidney. Its potency to produce
pancreatic carcinomas that morphologically and
biologically were identical to human pancreatic
cancers was remarkable. Since the induction of
tumors in other tissues and in a high incidence
restricted its value as a model for pancreatic
cancer, several studies were set-up to minimize or
ideally prevent tumor formation in tissues other
than the pancreas. Modification of the BHP dose
had limited success. A dose as low as 1/40 of the
LD50 induced tumors primarily in the pancreas
followed by the liver. Higher doses exhibited a
more pronounced hepatocarcinogenicity and also
induced tumors in the respiratory tract, gall
bladder, kidney and vagina 153 . These findings led
Krüger to assume that the β position of the DPN
chain determines its target tissue and the βoxidation
of one chain could be more specific to
the pancreas. Accordingly, he initially synthesized