Shahrokh Salmasi

Current knowledge of pancreatic carcinogenesis in the hamster and its relevance to the human disease

Syrian hamsters present a unique species for induction of pancreatic tumors that in many aspects resemble human pancreatic cancer. The specific response of Syrian hamsters, in contrast to many other rodents, for development of pancreatic ductal (ductular) tumors is not yet known. All pancreatic carcinogens thus far tested show certain common features. They are all nitrosamines that possess or can be metabolized to compounds with 2‐oxopropyl‐ or 2‐hydroxypropyl substituents. All but one, N‐nitrosomethyl(2‐oxopropyl)amine, occur or metabolize to nitrosamines with the ability to cyclize and form structures resembling glucose. Hence it is suggested that this cyclic structure may be responsible for the pancreatic carcinogenicity of these nitrosamines, as has been proposed for the pancreatotropic effect of streptozotocin. It is also of further interest that one pancreatic ductal (ductular) carcinogen, N‐nitroso‐2‐methoxy‐2,6‐dimethylmorpholine, which possesses a totally cyclic structure, acts, like streptozotocin, as β‐cell cytotoxic and diabetogenic when given in a high single dose. Modification of pancreatic tumor induction has been demonstrated by specific procedures. A high fat diet significantly increases both the incidence and number of induced cancers. Methods for early diagnosis and therapy are being developed and their significance and applicabilities for clinical use will be of major importance. Compared with the other most common types of human cancer, pancreatic cancer has extraordinary characteristics, which make the disease one of the most mysterious of maladies. Consequently, pancreatic cancer represents a serious international problem and requires urgent resolution, especially with regard to its etiology, early diagnosis, prevention, and therapy.

Selective induction of pancreatic ductular tumors by single doses of N-nitrosobis(2-oxopropyl)amine in syrian golden hamsters*

The selectivity of response by the Syrian hamster pancreas to the neoplastic effect of N-nitrosobis(2-oxopropyl)amine (BOP) was demonstrated by single subcutaneous injections of the compound. Only occasional tumors were induced simultaneously with those of the pancreas in the biliary ducts, kidneys and lungs of a few hamsters. In the pancreas, the ductules, especially those of an intrainsular location, were the cells primarily affected. The responded to doses as low as 1/40 of the LD50, whereas ductal lesions were found only in some hamsters treated with doses above 1/5 of the LD50. Hence it is concluded that hamster ductular cells are the most responsive to the carcinogenic action of BOP.

Tumor-initiating activity in mouse skin and carcinogenicity in rat mammary gland of fluorinated derivatives of benzo[a]pyrene and 3-methylcholanthrene

SummaryComparative studies of tumor-initiating activity in mouse skin and carcinogenicity in rat mammary gland were conducted with benzo[a]pyrene (BP) and 3-methylcholanthrene (MC) derivatives. SENCAR mice were initiated with BP, 6-fluorobenzo[a]pyrene (6-FBP), 6-methylBP, 7-FBP, 8-FBP, 9-FBP, 10-FBP, or 10-azaBP and promoted with tetradecanoyl phorbol acetate. The same compounds plus BP 7,8-dihydrodiol were tested by intramammillary injection in female Sprague-Dawley rats. Tumor-initiating activity in mice and/or carcinogenicity in rats were observed for BP, 6-methylBP, 6-, 7-, 8-, and 10-FBP, whereas 9-FBP was inactive in both experiments and 10-azaBP was only marginally active in the mammary gland. BP 7,8-dihydrodiol was carcinogenic in rat mammary gland, although it was less potent than BP. MC, 8-FMC, 10-FMC, and 3-methylcholanthrylene were also tested in Sprague-Dawley rats by intramammillary injection. All compounds were carcinogenic, with MC displaying the most potent activity. The less potent carcinogenic activity of BP 7,8-dihydrodiol in the mammary gland, compared with BP, and the moderate-to-weak tumor-initiating and/or carcinogenic activity of 7-, 8-, and 10-FBP suggest that the bay-region diol-epoxide pathway does not play a significant role in the activation of BP in these two target tissues. Similarly, the carcinogenic activity of 8-FMC and 10-FMC, in which the bay-region diol-epoxide pathway is blocked, suggests that this mechanism of activation is not important in the carcinogenicity of MC in rat mammary gland.

Ductular origin of pancreatic cancer and its multiplicity in man comparable to experimentally induced tumors. A preliminary study

The histologic features of 3 randomly selected pancreatic cancer cases are compared with those found in Syrian hamsters after treatment with N-nitrosobis(2-oxopropyl)amine (BOP). The 3 human cases all exhibited hyperplastic, preneoplastic and malignant changes which were markedly multicentric, and which arose predominantly from ductules, as well as from small ducts. The findings were comparable to those in the hamster mode. Proliferation and malignant alterations of the intrainsular ductules were commonly seen in both human and experimental tumors. The data is consistent with the concept that cells of the small ducts and especially of the ductules represent a potential source of human, as well as experimental, tumors. The small number of human cases studied does not allow generalization, but the marked resemblances in all 3 randomly selected pancreatic cancer cases were remarkable.

Carcinogenicity tests of acetoxymethylphenylnitrosamine and benzenediazonium tetrafluoroborate in Syrian hamsters

The metabolic activation of the esophageal carcinogen methylphenylnitrosamine (MPhN) via alpha-hydroxylation to hydroxymethylphenylnitrosamine (HO-MPhN) should afford benzenediazonium ion (BDI) as the ultimate electrophilic metabolite. To determine if this proposed activation pathway is accurate, BDI, as its tetrafluoroborate (BF4) salt, was tested by chronic subcutaneous injection and gavage in Syrian golden hamsters. Acetoxymethylphenylnitrosamine (AMPhN), which is rapidly hydrolyzed to HO-MPhN in vivo, was similarly tested by s.c. injection. AMPhN was weakly carcinogenic, while BDI-BF4 did not induce a significant tumor incidence by subcutaneous administration. When orally administered, BDI was inactive. Both AMPhN and BDI-BF4 were mutagenic only in Salmonella typhimurium strain TA1537 without enzymic activation. The parent nitrosamine, MPhN was also mutagenic in TA1537, but only with enzymic activation. The mechanistic and environmental significance of these results are discussed.

Tumorigenicity of 6-halogenated derivatives of benzo[a]pyrene in mouse skin and rat mammary gland

SummaryStudies of the tumorigenicity of 6-halogenated derivatives of benzo[a]pyrene (BP) can provide evidence about the role of the 6 position in the carcinogenic activation of BP. Female Swiss and A-strain mice were treated on the skin with BP, 6-fluorobenzo[a]pyrene (6-FBP), 6-chlorobenzo[a]pyrene (6-C1BP), 6-bromobenzo[a]pyrene (6-BrBP) and 6-iodobenzo[a]pyrene (6-IBP) by repeated application, and in some cases by initiation-promotion. While BP was more potent than 6-FBP, only these two compounds exhibites tumor-initiating and carcinogenic activity in mouse skin. Female Sprague-Dawley rats were treated with BP, 6-FBP, 6-C1BP, and 6-BrBP by intramammillary injection. BP and 6-FBP induced high levels of mammary epithelial tumors and fibrosarcomas. 6-C1BP elicited only a high percentage of fibrosarcomas, whereas 6-BrBP induced a few adenocarcinomas. These results indicate that chloro or bromo substitution at C-6 in BP reduces or eliminates carcinogenic activity. Conversely, 6-FBP, from which the fluoro substituent has been chemically and metabolically removed by one-electron oxidation, displays a moderate carcinogenic acitivity which is consistent with activation by either one-electron oxidation or monooxygenation.

Induction of benign and malignant lip tumors in Syrian hamsters by topical application of N-nitrosobis(2-oxopropyl)amine and N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine

Weekly topical application of equitoxic doses of N-nitrosobis(2-oxopropyl)amine (BOP) or N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP) to lip and/or vagina of female Syrian hamsters led to the development of papillomas and carcinomas of the lip, papillomas of the vagina, and tumors of internal organs. The relative incidence of the tumor types is affected by the dose of BOP or HPOP administered. BOP is excreted unchanged and as HPOP in the saliva of Syrian hamsters injected subcutaneously with BOP and pilocarpin. This result may help to explain preliminary observations that subcutaneously injected BOP and pilocarpin also lead to lip tumors.

Induction of local epidermal papillomas and carcinoma by selected nitrosamines

Weekly cutaneous application of N-nitrosobis (2-oxopropyl)amine (BOP) at a dose of 2 mg/application to the neck area resulted in the induction of local papillomas and carcinomas in 80% of Syrian hamsters as early as 19 weeks post-treatment. In addition, a few tumors of internal organs (predominantly in the liver) were also found. N-Nitroso(2-hydroxypropyl) (2-oxopropyl)amine (HPOP), a common metabolite of BOP and BHP, was also found to be an epidermal carcinogen at a dose of 3.8 mg/application. N-Nitrosobis(2-hydroxypropyl)amine (BHP), however, failed to induce any epidermal lesions, when applied similarly at a much higher dose level (%) mg/animal/week). In contrast to BOP and HPOP, BHP induced a high incidence of tumors in internal organs, especially pancreatic cancer, which was the only induced tumor in 5 animals. Skin absorption studies demonstrated that BHP, but not BOP is rapidly absorbed and was detectable in the blood in concentrations of up to 5.5 mug/ml as early as 15 min after carcinogen administration. The possible reasons for the differing effects of BHP and BOP upon hamster skin are discussed.

Anatomy, Histology, Ultrastructure, Parathyroid, Mouse

The parathyroids of mice, like those of the rat and hamster, are paired organs situated lateral to, and often lying in a depression of, the thyroid gland (Fig. 253). In strain OF1 the glands are frequently found as a solid mass (Fig. 254) or as elongated, fish-shaped structures. In some older animals a small gland, often hard to discern, can be detected embedded within thyroid tissue (Fig.255). In Swiss mice the glands are usually oval, 1.0×0.5 mm in dimension and difficult to detect grossly. They are generally surrounded by a thin, loose capsule, branches of which follow the capillaries within the gland. Occasional mast cells, fat cells and nonmyelinated nerve fibers are present in the delicate interstitium (Coleman and Silbermann 1978).

Anatomy, Histology, Ultrastructure, Parathyroid, Rat

Literature relative to the anatomy, histology, histochemistry, function, and diseases of the parathyroid glands in rats is voluminous. However, little information is available concerning the clinical and morphological criteria for defining the terms “hyperplasia” and “neoplasia”, a matter constituting a great handicap, especially in toxicologic pathology. The data presented here concentrate on the histopathology of the parathyroid glands in three rat strains and derive primarily from our routine autopsies. We have attempted to define criteria for hyperplastic and neoplastic changes by specific cytohistologic findings, which may not correlate, however, with the biologic character of the lesions.