PMID: 2118419Sep 15, 1990Paper

Potentiation of carcinogen-induced methotrexate resistance and dihydrofolate reductase gene amplification by inhibitors of poly(adenosine diphosphate-ribose) polymerase

Cancer Research
A BürkleH zur Hausen

Abstract

Poly(ADP-ribosyl)ation of nuclear proteins is an immediate response of most eukaryotic cells to DNA strand breaks, as induced by carcinogen treatment. DNA amplification, on the other hand, can be induced in cell culture systems by chemical or physical carcinogens, too, reaching peak levels a few days after induction treatment. We have previously shown that 3-aminobenzamide, an inhibitor of poly(ADP-ribosyl)ation, potentiates carcinogen-induced simian virus 40 DNA amplification in hamster cells which served as a short-term model system (Bürkle et al., Cancer Res., 47: 3632-3636, 1987). Here we report that those results can be extended to the development of methotrexate (MTX) resistance associated with dihydrofolate reductase (DHFR) gene amplification in a different hamster cell line. (a) Treatment with the alkylating carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) 3 days before selection with 350 nM MTX induced the MTX resistance frequency by 17- to 100-fold, as expected. Addition of 3-aminobenzamide (0.1 to 1 mM) before MNNG treatment further potentiated the frequency of MTX resistance by up to 5-fold in a dose-dependent manner, parallel to a potentiation of cytotoxicity. MTX resistance frequency was potentiated not only...Continue Reading

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