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At least 1,225 records · Page 68Linked to original sources
PubMed1988

Establishment and characterization of a cultured cell line derived from nitrosamine-induced pancreatic ductal adenocarcinoma in Syrian golden hamsters.

Seven kinds of pancreatic ductal adenocarcinomas induced by N-nitrosobis(2-hydroxypropil)amine in Syrian golden hamsters were established as transplantable tumor lines on syngeneic animals. These tumor lines were all well or moderately differentiated adenocarcinomas, showing various velocities of growth, unrelated to the grade of histological differentiation. A cell line, designated HaP-T1, was established in continuous tissue culture from one of these homografts. The cells grew in a monolayered sheet with an approximately 17-hour population doubling time. Chromosomal analysis revealed that the modal chromosomal number of the cell line was 44. HaP-T1 cells showed apparent tumorigenicity both on syngeneic hamsters and athymic nude mice, but they grew much faster when injected into the former animals. Morphological characteristics of HaP-T1 cells and tumors induced by HaP-T1 inoculation in both animals revealed apparent epithelial characteristics resembling ductal adenocarcinoma of the pancreas. These transplantable tumor models will contribute to the further investigation in the field of pancreatic cancer.

Animals↗
PubMed1986

Correlative histochemical studies on preneoplastic and neoplastic lesions in the kidney of rats treated with nitrosamines.

Renal tubular lesions induced in male rats by two different carcinogens, N-nitrosomorpholine (NNM) and N-ethyl-N-hydroxyethylnitrosamine (EHEN), using a limited exposure "stop" protocol were investigated histochemically to demonstrate phenotypic cellular changes. The parameters measured included basophilia, glycogen content and the activity of the enzymes glucose-6-phosphatase (G6PASE), glycogen synthetase (SYN), glycogen phosphorylase (PHO), glucose-6-phosphate dehydrogenase (G6PDH), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), succinate dehydrogenase (SDH), alkaline phosphatase (ALP), acid phosphatase (ACP) and gamma-glutamyl transpeptidase (gamma-GT). The lesions observed were predominantly of either basophilic or oncocytic types. In each case, tubular lesions (altered tubules) appeared to give rise to epithelial tumors (epitheliomas) with the same cellular phenotype. Basophilic tubules and epitheliomas proved to be strongly positive for GAPDH and G6PDH while demonstrating a reduction or loss of G6PASE, ALP, ACP, gamma-GT, and SDH compared with controls and the surrounding proximal or distal tubules. In addition, large basophilic epitheliomas demonstrated an increase in both SYN and PHO activities. In contrast, most oncocytic tubules and oncocytomas characterized by abundant densely granular cytoplasm showed a reduction in the activity of G6PDH, but were intensely positive for SDH. However, a few oncocytic lesions demonstrated a decrease in both SDH and G6PDH activity. Rarely, decreased SDH and elevated G6PDH activities were observed in altered tubules resembling oncocytic tubules. It remains to be clarified whether these tubules represent a variation of the oncocytic lesions or, perhaps, another type of tubular lesion. The results indicate that basophilic and oncocytic epithelial tumors differ in their cytochemical pattern and histogenesis. In line with earlier suggestions, the basophilic tumors apparently originate from the proximal renal tubules, while the oncocytomas develop from the distal parts of the nephron. The basophilic tumors are characterized by an increased pentose phosphate pathway and glycolysis, with a corresponding reduction in mitochondrial respiration. However, the majority of the oncocytomas show an increased activity of the mitochondrial enzyme SDH, and a marked decrease in the activity of the key enzyme of the pentose phosphate pathway.

Animals↗
PubMedDate not supplied

Combination treatment of nitrosamine-induced pancreatic cancers in hamsters with analogs of LH-RH and a bombesin/GRP antagonist.

Analogs of luteinizing hormone-releasing hormone (LH-RH) and bombesin/gastrin-releasing peptide were previously shown to inhibit the growth of experimental pancreatic cancers. In the present study, in an attempt to increase the efficacy of therapy, female Syrian golden hamsters with N-nitrosobis(2-oxopropyl)amine-induced pancreatic cancers were treated for 2 mo with a combination of LH-RH agonist [D-Trp6]LH-RH or antagonist [Ac-D-Nal(2)1, D-Phe(4Cl)2, D-Pal(3)3, D-Cit6-Ala10]LH-RH (SB-75) and bombesin/GRP antagonist D-Tpi6, Leu13 psi(CH2NH)Leu14bombesin(6-14) (RC-3095). The results were compared to those obtained by treatment with same doses of single peptides. LH-RH analogs and bombesin antagonist given alone significantly reduced the number of tumorous animals and decreased weight of pancreata by 46-71% and weight of tumorous pancreas by 38-64%. Histology showed lower mitotic activity and a decreased number of AgNORs in tumor cells from treated animals. Enhanced apoptosis was also observed after treatment with the LH-RH analogs. Combination therapy had no superior inhibitory effect on tumors compared to single peptides, by practically all the parameters analyzed. The reasons for this lack of potentiation are not clear. The tumor inhibitory effect of bombesin antagonists appears to be mediated by interference with EGF-receptor mechanisms. In the present study, although a significant downregulation of EGF-receptors was found in tumors treated with combination, the decrease in binding capacity for EGF was maximal in the group treated with RC-3095 alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

The effects of benzo(a)pyrene, nicotine, and tobacco-specific N-nitrosamines on the generation of human lymphokine-activated killer cells.

The effects of four major components of snuff (fine-cut smokeless tobacco) on the development of lymphokine-activated killer cells (LAK) were measured in vitro. Of the components tested: nicotine, N'-nitrosonornicotine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and benzo(a)pyrene (BaP), only BaP suppressed LAK cytotoxicity against tumour targets and LAK DNA synthesis during 3- and 7-day incubations. BaP concentrations of 0.1-1.0 micrograms/ml suppressed lymphocyte proliferation only; there was no effect on tumour cell proliferation at these concentrations. BaP had no effect on tumour target killing when incubated during 4 h natural killer (NK) or LAK cytotoxicity assays. There was no effect on LAK binding of tumour targets after 3 days culture with BaP concentration of 0.1-1.0 micrograms/ml. These data confirm that a water-soluble extract of snuff has anti-cytolytic and anti-proliferative effects on peripheral blood lymphocytes. As NK and LAK cells are important in preventing tumourigenesis and metastasis, suppression of these cells may favour neoplastic growth associated with snuff-dipping.

Benzopyrenes↗
PubMed1985

Relation between hepatic microsomal metabolism of N-nitrosamines and cytochrome P-450 species.

Effects of SKF 525A (0.1 mM), metyrapone (0.1 mM), alpha-naphthoflavone (ANF) (0.5 mM) and pyrazole (1.0 mM) on N-nitrosodimethylamine (NDMA), N-nitrosomethylbutylamine (NMBuA) and N-nitrosomethylbenzylamine (NMBeA) metabolism by hepatic microsomes from rats pretreated with inducers were investigated. NDMA demethylation was weakly increased by phenobarbital (PB) treatment. The demethylation was inhibited by SKF 525A and enhanced by metyrapone in non-treated and PB-treated microsomes, and weakly inhibited by ANF in 3-methylcholanthrene(MC)-treated microsomes. NMBuA demethylation was increased by PB treatment and inhibited by SKF 525A in all microsomes. Metyrapone inhibited the demethylation in PB-treated microsomes. NMBuA debutylation was increased by PB and MC treatments, and inhibited by metyrapone in all microsomes. The strongest inhibition by metyrapone was observed in PB-treated microsomes. The debutylation was inhibited by SKF 525A in non-treated and PB-treated microsomes and by ANF in MC-treated microsomes. NMBeA demethylation was decreased by MC treatment and weakly inhibited by SKF 525A in all microsomes. The effects of the inducers and inhibitors on NMBeA debenzylation were almost the same as those on NMBuA debutylation except that the increasing effect of MC was small. Pyrazole was a relatively selective inhibitor of NDMA demethylation. These results suggest the following: NDMA demethylation is catalyzed by PB-induced cytochrome P-450 species (P450-PB) and MC-induced cytochrome P-450 species (P448-MC). But their specific activity is low and the other cytochrome P-450 species demethylate NDMA. NMBuA demethylation is catalyzed by P450-PB. But the specific activity is not high and the other cytochrome P-450 species also demethylate NMBuA. NMBuA debutylation is catalyzed by P450-PB and P448-MC. Almost all of NMBeA demethylation is catalyzed by cytochrome P-450 species other than P450-PB and P448-MC. NMBeA debenzylation is catalyzed by P450-PB and P448-MC, but the specific activity of P448-MC is not high.

Animals↗
PubMed1978

Nitrosamine carcinogenicity: a quantitative Hansch-Taft structure-activity relationship.

Statistically significant correlations have been demonstrated between carcinogenic activity, water-hexane partition coefficients and electronic factors for an extensive series of N-nitroso compounds. Electronic factors were expressed by the Taft sigma* values of substituents on the carbon atoms alpha to the N-nitroso group. Such correlations indicate that transport of the carcinogen to its active site has an important effect on its potency. The correlations also implicate reactivity at the alpha-carbon in the determination of carcinogenic activity and point out various structural types which do not follow the general rule.

Animals↗