Lawrence Wallcave

Ascorbate-Nitrite Reaction: Possible Means of Blocking the Formation of Carcinogenic N-Nitroso Compounds

The formation of carcinogenic N-nitroso compounds by the chemical reaction between nitrous acid and oxytetracycline, morpholine, piperazine, N-methylaniline, methylurea, and (in some experiments) dimethylamine was blocked by ascorbic acid. The extent of blocking depended on the compound nitrosated and on the experimental conditions. Urea and ammonium sulfamate were less effective as blocking agents. The possibility of in vivo formation of carcinogenic N-nitroso compounds from drugs could be lessened by the combination of such drugs with the ascorbic acid.

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.

Skin tumorigenesis in mice by petroleum asphalts and coal-tar pitches of known polynuclear aromatic hydrocarbon content

Abstract Benzene solutions of eight petroleum asphalts and two coal-tar pitches of known polynuclear aromatic hydrocarbon content were applied topically to Swiss mice. Epidermal carcinomas and papillomas were observed in over 90% of coal-tar pitch treated animals. Only one carcinoma and 5 papillomatous growths were observed in 218 mice treated with asphalts. The relatively low tumor incidence resulting from the asphalt treatments precluded an evaluation of a possible relationship between polynuclear aromatic hydrocarbon content and tumorigenicity. An analytical method for determining the polynuclear aromatic hydrocarbon content of asphalt and coal-tar pitch is presented, and values are given for 17 such compounds in each of the test materials.

Common metabolites of N-nitroso-2,6-dimethylmorpholine and N-nitroso-bis(2-oxopropyl)amine in the Syrian hamster

N-Nitroso-2,6-demethylmorpholine (NDMM) administered intraperitoneally to Syrian hamsters was metabolized to N-nitroso-bis(2-hydroxypropy)(2-oxopropyl)amine(HPOP) and N-nitroso-bis(2-hydroxpropyl)amine (BHP) which were identified in blood and urine. The potent pancreatic carcinogen N-nitroso-bis(2-oxoproply)amine was previously shown to form the same metabolites. Preliminary results indicate that NDMM also induces pancreatic and other tumors in Syrian hamsters, similar to those found following BHP treatment.

The carcinogenicity of N-nitrosodiethanolamine, an environmental pollutant, in Syrian hamsters.

Weekly subcutaneous injections of N-nitrosodiethanolamine (NDELA) at doses of 1000, 500 and 250 mg/kg body wt for life induced tumors in Syrian hamsters which primarily affected the upper respiratory tract. The incidence of these malignant neoplasms arising exclusively from the olfactory region was between 73% (highest dose) and 35% (lowest dose). Lower numbers of neoplasms were found with decreasing frequency in the trachea, larynx and lungs. The results indicate that doses of NDELA lower than 250 mg/kg body wt may also be carcinogenic. Hence, NDELA and its precursors should be regarded as hazardous to human health.

Carcinogenic bioassay of oil shale: Long-term percutaneous application in mice and intratracheal instillation in hamsters

Abstract The carcinogenic potential was evaluated of selected oil shale samples: Shale oil coke, spent oil shale, raw oil shale, lift pipe effluent, and processed shale by skin painting in mice and intratracheal instillation in Syrian hamsters. Of the four samples tested in mice, only the benzene extract of shale oil coke exhibited a definite carcinogenic effect by inducing epidermal carcinomas and papillomas in 96% of the mice. There were six tumor-bearing animals in the spent oil shale extract-treated group and a single papilloma in the group treated with lift pipe effluent extract. The raw oil shale extract failed to induce any skin tumors. The tumor incidences resulting from treatment with oil shale samples indicated a possible association between the benzo( a )pyrene content in the samples and tumorigenicity. In this study, at the given dose levels, repeated intratracheal instillation of oil shale solids induced no toxic or carcinogenic effects in the respiratory tract of hamsters.

A rapid method for isolating phorbol from croton oil

The published method for isolating phorbol from croton oil has been improved and made more rapid, mainly by the addition of silica-gel column chromatography. The spectral characteristics are recorded, including the 13C nuclear magnetic resonance (NMR) spectrum.

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.

Alpha-acetoxy derivatives of methyl-2-oxopropylnitrosamine: Synthesis, hydrolysis rate and bacterial mutagenicity

N-Methyl-N-2-oxopropylnitrosamine (MOP) induces pancreatic tumors in hamsters. As models for the putative proximate carcinogenic alpha-hydroxy derivatives, we studied N-acetoxymethyl-N-2-oxopropylnitrosamine (AMOP) and N-methyl-N-(1-acetoxy-2-oxopropyl)nitrosamine (MAOP). AMOP was synthesized from aminoacetone by the method of Roller et al. [1975), Tetrahedron Lett., 25, 2065-2068) and MAOP was synthesized by acetoxylation of MOP with lead tetraacetate. The half-lives of AMOP, MAOP and acetoxymethylmethylnitrosamine (ADMN) in aqueous buffer decreased as the pH rose from 5 to 9, with values at pH 5 of 2.8 X 10(4) min for AMOP, 3.2 X 10(3) min for ADMN, and 23 min for MAOP. Mutagenicity was examined in Salmonella typhimurium TA1535, using a pre-incubation at pH 5 without microsomal activation. The mutagenic potency, expressed as revertants/mumole, was 56 for AMOP, 150 for ADMN, and 4.5 X 10(4) for MAOP. Hence, hydrolysis rates at pH 5 were probably important in determining the relative mutagenicity.

The effect of N-nitroso-2-methoxy-2,6-dimethylmorpholine on endocrine and exocrine pancreas of Syrian hamsters.

N-Nitroso-2-methoxy-2,6-dimethylmorpholine (MeNDMM), a cyclic derivative of the proposed proximate pancreatic carcinogen N-nitroso(2-hydroxypropyl) (2-oxopropyl)amine (HPOP), is shown to have an almost selective cytotoxic effect on pancreatic beta-cells when a single high dose is given to Syrian hamsters. Hence in this aspect its effect is comparable to that of streptozotocin, which has a glucose moiety similar to the MeNDMM structure. However, contrary to the effect of streptozotocin, low single (subdiabetogenic) doses of MeNDMM led to the development of pancreatic ductular and mixed ductular-insular neoplasms; only 1 animal also had islet cell adenoma. It therefore seems that MeNDMM possesses an affinity for both endocrine and exocrine pancreatic tissue. Other target tissues of MeNDMM were the forestomach, intra- and extrahepatic bile ducts, liver, kidneys and vagina. The tumors of these organs appeared in various incidences, partially in relation to dose and/or survival time. The possible mechanisms of the MeNDMM effect upon the endocrine and the exocrine pancreas is discussed.