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Mechanisms of Resistance in a Human Cell Line Exposed to Sequential Topoisomerase Poisoning¹

Departments of Pharmacology and Medicine, Robert Wood Johnson Medical School and The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey 08901 [A. S., N. I., M. P., X-G. L. E. G., E. H. R.] and The Stehlin Foundation for Cancer Research, Houston, Texas 77002 [J. M., P. P.]

Camptothecins are a new class of anticancer drugs that target DNA topoisomerase I; current efforts are directed toward elucidating optimal combinations of these drugs with other antineoplastic agents. A rationale for the use of sequential therapy involving the combination of camptothecins with topoisomerase II-targeting drugs, such as etoposide, has arisen from observations of increased topoisomerase II protein levels in cell lines resistant to camptothecin. In an effort to understand potential mechanisms of resistance to this strategy, we developed a U-937 cell subline, denoted RERC, that is capable of surviving exposure to sequential topoisomerase poisoning. The RERC cells are 200-fold resistant to camptothecin, 8-fold resistant to etoposide, and 10-fold hypersensitive to cisplatin compared to the parental U-937 cells. Biochemical analyses indicate that the resistant phenotype involves alterations in both topoisomerase I and topoisomerase II. Topoisomerase I catalytic activity in the resistant cells is similar to that of the parental line but is resistant to camptothecin. Moreover, the resistant cells express a single mRNA species of topoisomerase I that codes for a mutation in codon 533. In addition, topoisomerase II protein levels are decreased 10-fold in the resistant line, coincident with a two-fold decrease in the expression of topoisomerase II mRNA. Collectively, these results indicate that resistance to sequential topoisomerase poisoning may involve a reduction in total cellular topoisomerase activity.

¹ This investigation was supported by USPHS Grants CA70981 and CA71535 (to E. H. R.), awarded by the National Cancer Institute.

² To whom requests for reprints should be addressed, at Department of Pharmacology, Robert Wood Johnson Medical School and the Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901.

Received 7/27/97. Accepted 9/22/97.

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