Repeated Dose Treatment Research Articles

ALTERATION IN THE CAPACITIES OF CARCINOGEN METABOLIZING SYSTEM OF MOUSE-LIVERS DURING PRETREATMENT WITH VARIOUS ANTINEOPLASTIC AGENTS

The effect of treatment with antineoplastic drugs on the modification of the carcinog en-metabolizing capacity was studied in mice liver microsomes at different durations as a single and as a repeated dose treatment. It is generally demonstrated that there is a commonality of influence for each specific antineoplastic group on the expression of the mixed function mono-oxygenases. The antineoplastic alkylating agents (chlorambucil, melphalan and busulfan) significantly increased the activity of carcinogen metabolizing enzymes in contrary to the effects observed for the antibiotic actinomycin-D. The antimetabolite agents (5-flourouracil and methotrexate), on the other hand, although decreased these activities when administered as a single dose, a pronounced increase was observed at the repeated dose treatment. Significant increases in the activity of N-nitrosodimethylamine demethylases I and II and aryl hydrocarbon (benzo[alpha]pyrene) hydroxylase were observed with chlorambucil when administered as a single or repeated doses. Similar effects was observed when the animals were treated with repeated doses of melphalan, busulfan and 5-flourouracil. Contrary to these effects, inhibition in the enzyme activity was exhibited when actinomycin-D was administered for either single or repeated dose treatment. The hepatic content of cytochrome P450 was significantly increased with all the administered drugs, except busulfan, when applied repeatedly. The implication of such alterations in the capacities of carcinogen metabolizing enzymes for antitumour-induced toxicity and carcinogenicity are discussed.

IN-VIVO AND IN-VITRO EVALUATIONS FOR THE EFFECT OF CYCLOPHOSPHAMIDE ON THE CARCINOGEN METABOLIZING SYSTEM OF MOUSE-LIVER MICROSOMES

The effect of the antineoplastic immunosuppressive alkylating agent cyclophosphamide (CPhA) on the modification of the carcinogen-metabolizing capacity was studied in vivo in mouse liver microsomes at different durations of treatment, from one to six consecutive days. The in vitro effect of increasing concentrations of the drug upon this enzyme system was also investigated. Following the administration of CPhA, a significant time-dependent decrease was observed in the activity of the low substrate level of the hepatic microsomal N-nitrosodimethylamine demethylase (NDMAdII). The high substrate level of the enzyme (NDMAdII) also exhibited a similar decrease which was not a subject for the treatment intervals where the greatest decrease (-60%; p<0.05) emerged at day 3 of the administration-point. The activity of the aryl hydrocarbon (benzo(alpha)pyrene) hydroxylase (AHH) revealed a significant increase at the single dose of CPhA, while at the repeated dose treatment (for 3 days) no alteration was noticed in the enzyme activity. This figure of expression in AHH was reversed to a significant inhibition at the 6 day-repeated dose, the time-point at which an almost identical effect was also observed in the hepatic content of cytochrome P450. The alterations in the metabolism of NDMA and benzo(alpha)pyrene which had been seen in the in vivo assays was further confirmed by the results of the in vitro experiment.

In vivo studies on the effect of some insecticides on the hepatic activities of l-tryptophan 2, 3-dioxygenase and pyridoxal phosphokinase of male mice

The effect of Dimethoate, Carbaryl and Permethrin on the activities of liver L-tryptophan 2,3-dioxygenase (total-, holo-, and apo-forms) and pyridoxal phosphokinase of male mice was investigated. Dimethoate inhibited both enzyme systems after single and repeated dose treatment; except the dioxygenase holo-enzyme after repeated doses. Single dose of Carbaryl treatment inhibited the pyridoxal phosphokinase, total and holo-enzyme of L-tryptophan dioxygenase. However, the repeated dose treatment do not affect both enzyme systems. Permethrin inhibited only total-, holo- and apo-enzymes of L-tryptophan dioxygenase whereas repeated administration has no significant effect on both enzymes. The data indicate that these insecticides may induce abnormal tryptophan metabolism through which some endogenous bladder carcinogens are formed.

Kurloff cell levels in the peripheral blood of normal guinea-pigs treated with cytotoxic drugs.

The effect of cytotoxic drugs on Kurloff cell levels in the peripheral blood of normal female guinea-pigs has been studied. Single doses of cyclophosphamide, azathioprine, methotrexate, busulphan and melphalan all failed to reduce Kurloff cell levels. Repeated high dose treatment with cyclophosphamide caused a significant fall in circulating Kurloff cells, but also resulted in the dealth of animals. The similarity between these findings and those obtained by other authors using whole body radiation is discussed. The results show that Kurloff cells are much more resistant than some lymphocyte populations to the effect of cytotoxic drugs.