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Research has been conducted on the organosulfur compounds. The use of reagents in preparing thioamides, thioketones and thiolactams and the utility of P (sub)4 S (sub)10/hexamethyldisiloxane as a thionating agent are discussed.

Using the technique of alkaline elution analysis, the ability of 11 known or suspected pancreatic carcinogens to damage the DNA of pancreatic acinar cells when administered to rats and hamsters was examined. The two species respond differently to several agents. In selected instances, DNA damage was also assessed in cultured pancreatic acinar cells exposed to the agents. Comparisons of DNA damage produced with that produced gave useful information on the role of pancreatic metabolism in activating pancreatic carcinogens. Finally, information germane to the question of the cell of origin for pancreatic cancer was obtained. [ABSTRACT FROM PUBLISHER]

The effects of pyridoxal deficiency on the genotoxlclty and nodule inducing ability of azaserine in rat pancreas were examined. Azaserine at a dose of 10 mg/kg body weight which causes substantial DNA damage in normal rat pancreas, failed to induce DNA damage detectable by alkaline elution in the pancreas of pyridoxai-deficient rats. Studies of the distribution of [C]azaserine in rat tissues revealed that uptake of azaserine in pancreas of pyridoxal deficient rats was not significantly different from that of normal rats. The ability of a structurally unrelated amino acid carcinogen N-(N-methyl-N-nitrosocarbamoyl)-L-ornithine to damage rat pancreatic DNA was not affected by pyridoxal deficiency. In another study, the pyridoxal antagonist 4'-deoxypyridoxine was administered i.p. to rats prior to and during azaserine treatment. Four months later, quantitative stereological analysis of atypical acinar cell nodules revealed that there was a significant reduction in the number but not size of nodules in the pancreases of 4'-deoxypyridoxine-treated rats. These results confirm the relationship of the induction of DNA damage by azaserine to its ability to induce pancreatic tumors, and support previous studies of azaserine metabolism, strongly suggesting that the activation of this carcinogen is pyridoxal dependent. [ABSTRACT FROM PUBLISHER]

Utilizing the technique of alkaline elution analysis, the ability of N-nitrosomethyl(2-oxopropyl)amine (MOP), a potent pancreatic carcinogen, to damage pancreatic DNA in rats and hamsters was examined. Pancreatic DNA isolated from hamsters exposed for 1 h to MOP given i.p. at doses of 7–60 mg/kg showed dose-related DNA damage. A similar dose-response was observed in the pancreas of rats receiving 20 — 180 mg MOP/kg, suggesting that hamsters were 2–3 times more sensitive than rats. In contrast to the results obtained , functionally viable acinar cells from both rat and hamster pancreas, when exposed to levels of MOP comparable to those (20–180 μ/ml), failed to show dose-related DNA damage. Acinar cells from hamsters pretreated with 5, 6-benzoflavone, an inducer of cytochrome P-450 activity, showed greatly enhanced drug-metabolizing capability, but again no DNA damage was observed upon exposure to MOP. Minced hamster or rat pancreas also failed to show DNA damage in response to MOP treatment. When hamsters in which hepatic blood supply was interrupted by ligation were given 60 mg/kg MOP i.v. and sacrificed 15 min later, damage to pancreatic and liver DNA was comparable to that observed in ligated controls which had received saline only. Administration of MOP to sham-operated animals led to extensive DNA damage in both pancreas and liver at 15 min. Analysis by h.p.l.c. showed an almost Mold increase in the amount of MOP present in the pancreases of the liver-ligated animals as compared to the sham-operated unligated animals. MOP was absent from the liver of the ligated animals. These experiments strongly suggest that DNA damage by MOP to the pancreatic acinar cells and probably to other pancreatic cell types, as well, requires metabolic activation by the liver. [ABSTRACT FROM PUBLISHER]

Dithiolethiones are an important class of cancer chemopreventive agents. More than 50 new dithiolethione analogs were synthesized for structure-activity studies. Using selected dithiolethiones, studies were designed to measure protection against the hepatotoxicity of aflatoxin B1 (AFB1) and relate it to the protection against carcinogenicity. Young male F344 rats were pretreated with 0.1 or 0.3 mmol dithiolethiones/kg body wt and challenged with toxic doses of AFB1 (50 μg/100 g rat/day) on 2 successive days. One day later, the protection from hepatotoxicity was assessed by measuring serum hepatic enzymes, hepatic necrosis, and degree of bile duct cell proliferation. The ability of these dithiolethiones to prevent AFB1-induced tumorigenicity was assessed by quantifying the hepatic burden of putative preneoplastic lesions [placental glutathione S-transferase (GST-P)-positive foci]. Significant correlations (p < 0.01) were observed between these toxicological indices and GST-P focal burden (alanine aminotransferase, r = 0.943; sorbitol dehydrogenase, r = 0.897; histological index, r = 0.893; bile duct cell proliferation, r = 0.933). These results imply that inhibition of hepatotoxicity affords protection against hepatocarcinogenicity. The extent of protection from acute hepatotoxicity offers a simple, short-term biological endpoint to screen dithiolethiones and related compounds for their chemopreventive properties. [ABSTRACT FROM AUTHOR]

DNA damage was demonstrated by alkaline elution analysis in pancreas of rats treated with 100 mg/kg N-nitrosobis(2-oxopropyl)amine (BOP) and 20 mg/kg N-nitroso(2-hydroxy-propyl)2-oxopropyl)amine (HPOP). Young rats were treated with a single dose of BOP or HPOP and autopsied 4 months later. Histologically the pancreases contained multiple foci and nodules of atypical acinar cells which were not seen in controls. [ABSTRACT FROM PUBLISHER]