Frequencies of independent and simultaneous selection of Chinese hamster cells for methotrexate and doxorubicin (adriamycin) resistance.

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Abstract
We have determined the frequency with which Chinese hamster cells become resistant to either methotrexate or doxorubicin (former generic name, adriamycin) alone or to the acquisition of simultaneous resistance is 10-100 times higher than that predicted from the frequency of each resistance selected independently. In .apprxeq. 50% of cloned resistant variants, resistance is the result of amplification of the dihydrofolate reductase gene (methotrexate) and/or of the multiple-drug-resistance P-glycoprotein gene (doxorubicin). Prior exposure of cells to hypoxia markedly enhances these resistance frequencies. Our results indicate that the simultaneous emergence of resistance to these two cancer chemotherapeutic agents are not independent events, and we interpret them to constitute two consequences of the same basic process occurring at a high frequency.