Abstract
Eleven methasquin-resistant sublines were selected in vitro from a Chinese hamster cell line and maintained at drug concentrations of 0.01–50.0 μg/ml. Dose-response data showed that increases in resistance ranged from 6- to 6500-fold and that all sublines were cross-resistant to methotrexate. Dihydrofolate reductase activity was elevated 3- to 165-fold in the 11 methasquin-resistant lines. Relationships between drug response and enzyme activity suggested that for 6 sublines increased dihydrofolate reductase may be the primary determinant of response, whereas additional factors such as quantitative change in other tetrahydrofolate enzymes may influence resistance to antifolate in the other 5. Karyotype analysis of conventionally stained metaphase cells revealed the presence of nonuniformly altered chromosomes. Strikingly long chromosome segments were found on 1 homologue of chromosome 2 or 4 as a consistent feature of most, but not all, of the 11 methasquin-resistant sublines. The similarity of these findings to those previously reported for methotrexate sublines and more recent results obtained by trypsin-Giemsa banding analysis provide evidence of specific chromosomal alteration associated with increased intracellular dihydrofolate reductase.
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