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Modulation of cis-Platinum Resistance in Friend Erythroleukemia Cells by c-myc¹

Departments of Radiation Oncology [M. D. S.] and Pediatrics and the Committee on Cellular and Molecular Biology [E. V. P.], University of Michigan Medical School, Ann Arbor, Michigan 48109

The molecular genetic basis for cancer cell resistance to the important family of platinum coordination complex drugs is poorly understood. The observation that malignant cells commonly become resistant to therapy, while normal cells rarely do, suggests that certain molecular processes involved in malignancy, e.g., oncogene activation, might also play a role in drug resistance. Since aberrant expression and amplification of various myc oncogenes have been implicated in the prognosis of human cancers, the poor therapeutic response of some of these tumors might be explained if high levels of myc gene products rendered cells more refractory to therapy. We tested this hypothesis by determining the effect of varying the level of c-myc expression on resistance to cis-platinum and ionizing radiation in Friend murine erythroleukemia cells expressing varying levels of c-myc gene product. We found that a) the degree of cis-platinum resistance correlated directly with the level of c-myc expression, b) glucocorticoid induction of murine mammary tumor virus promoter-driven c-myc sequences significantly increased cis-platinum resistance, c) restoring c-myc transcript levels to normal restored the original cis-platinum sensitivity at a rate which paralleled that of induced c-myc transcript depletion, and d) c-myc transcript level had no effect on ionizing radiation response. These findings suggest that c-myc levels may influence therapeutic success in some tumors and may regulate specific processes by which cells cope with DNA damage caused by DNA cross-linking agents such as the platinum analogues, but not ionizing radiation.

¹ This work was supported by a grant from Bristol-Myers Squibb (M. D. S.) and NIH Grant R01HL33741 (E. V. P.).

² To whom requests for reprints should be addressed, at 2246 Pine Grove Court, Ann Arbor, MI 48103.

Received 7/30/90. Accepted 2/ 6/91.

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