The biochemical mechanisms of resistance to
CRC 680578, a new antitumour chloroethylnitrosourea alpha-
amino acid derivative, were studied. Alterations in
DNA,
RNA and
protein syntheses, SH-group content,
drug efflux, activities of replicative and repair
enzymes, such as
ribonucleotide reductase,
thymidine kinase, O6-alkylguanine-DNA-alkyltransferase and
DNA polymerases alpha and beta and damages of the
DNA secondary structure were investigated in sensitive and resistant to
CRC 680578 leukemia L1210 cells. It was found that the total SH-group number in
drug-resistant cells was increased (about 1.3-fold in comparison with sensitive cells) which seems to be due to the mechanisms of drug resistance. CHC 680578 induced less pronounced inhibition and more rapid restoration of
DNA and
RNA synthesis in resistant cells. No differences between the
ribonucleotide reductase and
thymidine kinase activities were found either in intact cells of the both strains or after
drug administration. The efficiency of repair of
DNA chloroethyl adducts by O6-alkylguanine-DNA-alkyltransferase in
leukemia cells of various sensitivity was found to be identical. The differences in
enzyme activities in intact cells of the both strains were insignificant. It was supposed that factors other than changes in the level of O6-alkylguanine-DNA-alkyltransferase in
leukemia cells may be responsible for the resistance to
CRC 680578. The increase in the levels of
DNA polymerase alpha and, especially, of
DNA polymerase beta, in sensitive (but not resistant) mouse
leukemia cells 48 hours after
drug administration is though to define the mechanism of resistance to the new antitumour agent CHC 680578.