Carcinogenesis
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Concurrent administration of para-aminobenzoic acid (PABA) reduced the toxicity of cis-diamminedichloroplatinum(II) (DDP) in a dose-related manner in rats. When administered i.p. simultaneously with 7.5 mg/kg DDP, PABA (100 mg/kg) significantly reduced plasma urea nitrogen (PUN) and plasma creatinine levels as well as DDP-induced weight loss. Increasing doses of PABA (25, 50 and 100 mg/kg) correlated with progressively better parameters of renal activity and body wt and with lower levels of platinum in plasma and tissues in rats killed 5 days after drug administration. ⋯ Analysis of tissue platinum content demonstrated significantly lower platinum levels both in kidneys (P < 0.05) and testes (P < 0.01) of mice receiving DDP and PABA in normal saline compared to those receiving only DDP in normal saline. PABA did not affect the in vivo and in vitro antitumor activity of DDP against P388 leukemia, and there was no significant PABA-induced modification in the concentration of platinum both in the tumor cells and in DNA samples isolated from P388 leukemic cells of DDP-treated mice. We conclude that PABA may be a promising compound for reducing DDP-toxic side effects, including nephrotoxicity, without compromising its antitumor activity.
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Several tumour promoting chemicals have been shown to inhibit intercellular communication (IC) through gap junctions in cell cultures. In the present investigation we studied the effect of the hepatic tumour promoters phenobarbital (PB), 1,1,1-trichloro-2,2-(p-chlorophenyl)ethane (DDT) and gamma-hexachlorocyclohexane (lindane) on IC in rat hepatocyte cultures. IC was evaluated by microinjection of fluorescent Lucifer Yellow CH dye and visualization of dye spread to adjacent hepatocytes. ⋯ The results indicate significant differences in the action of PB, DDT and lindane on IC in hepatocyte cultures. This is suggested by the differential effects of superoxide dismutase and non-steroidal anti-inflammatory agents on the action of the three tumour promoting chemicals. Whereas superoxide radicals may be involved in the inhibition of dye-coupling by PB, radical intermediates of the insecticides may be responsible for the decrease in dye-coupling by DDT and lindane.
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The metabolism of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was examined in the patas monkey, in order to provide further information about NNK metabolic pathways in primates. Female patas monkeys were given i.v. injections of [5-3H]NNK, and metabolites in serum and urine were analyzed by HPLC. Metabolism by alpha-hydroxylation of NNK was rapid and extensive, and the products of this pathway, 4-hydroxy-4-(3-pyridyl)butyric acid and 4-oxo-4-(3-pyridyl) butyric acid, accounted for a relatively large proportion of serum and urinary metabolites at all time points. ⋯ The two NNAL glucuronides accounted for 15-20% of the urinary metabolites in monkeys given 0.1 micrograms/kg NNK, which is similar to a smoker's dose, suggesting their use as dosimeters of NNK exposure in humans. Pharmacokinetic parameters were consistent with those observed in previous studies of nitrosamines, and varied predictably with body weight of five species. The results of this study have provided new insights relevant to assessing human metabolism of NNK.
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The aim of these studies was to determine the levels of carcinogenic tobacco specific nitrosamines (TSNA) in Sudanese oral snuff (toombak) as recent retrospective epidemiological studies suggested an association between the use of toombak and subsequent development of oral cancer. We have analyzed the TSNA levels in 20 samples of Sudanese toombak, of four different quality levels, collected from five different vendors. Using GC coupled with thermal energy analysis, four TSNA were quantified in snuff extracts: N'-nitrosonornicotine (NNN), N'-nitrosoanatabine (NAT), N'-nitrosoanabasine (NAB) and 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK). ⋯ Previously, the highest levels of NNN and NNK reported in any snuff were 0.154 and 0.014 mg/g dry wt respectively. In comparison, the levels in Sudanese toombak were up to 20 and 560 times higher respectively. As the public health implications of these findings are significant, attempts should be made to reduce exposure to TSNA in oral snuff users in Sudan.
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The effect of phenethyl isothiocyanate (PEITC), a dietary inhibitor of carcinogenesis, on the metabolism of the tobacco specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by cultured rat peripheral lung tissues was investigated. Initially, the metabolism of NNK by the tissues was studied by incubating the lung explants in medium containing 1 and 10 microM [5-3H]NNK for 3, 6, 12, and 24 h. NNK metabolites were analyzed and quantified by HPLC and expressed as nmol/mg DNA. ⋯ In general, the inhibition of NNK metabolism was greater when the explants were pre-treated with PEITC. These results suggest that PEITC is an effective inhibitor of the conversion of NNK to metabolites that elicit DNA damage. Our results are in agreement with previously published data in which PEITC was shown to inhibit NNK metabolism and tumorigenesis in the rat lung.