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Drug Response, Dihydrofolate Reductase, and Cytogenetics of Amethopterin-resistant Chinese Hamster Cells in Vitro¹

Division of Drug Resistance, Sloan-Kettering Institute for Cancer Research, New York, New York 10021

A graded series of amethopterin-resistant sublines maintained at concentrations varying from 0.1 to 50.0 µg/ml were selected in vitro from several parental Chinese hamster lines. Increases in resistance ranged from 45- to 108,400-fold. Dose-response data for sensitive and resistant populations demonstrated that the 3 parental lines responded identically to amethopterin and methasquin, while some but not all resistant sublines were widely divergent. Even though every resistant subline was cross-resistant to the quinazoline antifolate, methasquin was relatively effective against cells highly resistant to amethopterin and was the stronger growth inhibitor. Supplementation with thymidine (30 µM) in sensitivity assays with amethopterin did not alter response of cell lines to this agent.

Dihydrofolate reductase activity was elevated in the 9 resistant sublines. Relationships between drug response and enzyme activity appeared to differentiate cell lines into 2 groups with respect to each antifolate. The data suggest that increased levels of dihydrofolate reductase may be the primary determinant of response for some sublines whereas for others additional factors such as different enzyme form or altered transport may also influence sensitivity to drug. Disparate response of several of the sublines to the 2 agents implies separate mechanisms of uptake.

Cytogenetic analysis revealed considerable structural rearrangement of karyotype, characterizing each resistant subline. Chromosome numbers remained in the diploid range. Although there was suggestion of preferential alteration, with translocation of long chromosomal fragments, a possible association between specific karyotypic change and elevated dihydrofolate reductase level in amethopterin-resistant cells was not verified in this study.

¹ This investigation was supported in part by USPHS Research Grant CA 08748 and by the American Cancer Society Grant T-107.

Received 8/ 2/71. Accepted 9/17/71.

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