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Camptothecin Resistance Involving Steps Subsequent to the Formation of Protein-Linked DNA Breaks in Human Camptothecin-resistant KB Cell Lines¹

Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520

To identify mechanisms of camptothecin (CPT) resistance/toxicity, sublines from a human KB cell line were made resistant to CPT by continuous selection in increasing concentrations of CPT. Two CPT-resistant lines, 100 and 300, were 32- and 54-fold resistant to the growth-inhibitory properties of CPT compared to the KB line. After CPT-free culturing, partial revertant lines were established from each resistant line. These partial revertant lines, 100^rev and 300^rev, were 2.5- and 3.2-fold resistant to CPT compared to KB. When growth inhibition and toxicity were compared, the resistant lines alone displayed an enhanced cytostatic response to CPT. The resistant and partial revertant lines displayed no cross-resistance to etoposide or cisplatin. Comparisons of topoisomerase I (TOP1) activity, content, and protein-linked DNA break production by CPT revealed that resistant and partial revertant lines had one-half the levels as KB, with TOP1 activity that was equally sensitive to CPT in all cell lines tested. However, double-stranded DNA break induction by CPT was significantly reduced only in the resistant lines. Coincubation with 3-aminobenzamide, an inhibitor of poly(ADP-ribosyl) polymerase, potentiated CPT toxicity in the resistant lines alone, without affecting CPT: TOP1 interactions. Therefore, CPT resistance in the 100 and 300 lines was characterized by factors independent of TOP1, specific for CPT, and attenuated by poly(ADP-ribosyl) polymerase inhibition. This resistant phenotype produced fewer double-stranded DNA breaks and enhanced a cytostatic response to CPT.

¹ This research was supported by NCI Grant CA-44358.

² Present address: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109.

³ Present address: TriService General Hospital, Taipai, Taiwan, Republic of China.

⁴ Present address: Department of Oncology and Therapeutic Research, City of Hope National Medical Center, Duarte, CA 91010.

⁵ To whom requests for reprints should be addressed, at Yale University, Department of Pharmacology, School of Medicine, Sterling Hall of Medicine, P.O. Box 208066, New Haven, CT 06520-8066.

Received 7/13/95. Accepted 11/13/95.

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