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Enhancement of Anthracycline Growth Inhibition in Parent and Multidrug-resistant Chinese Hamster Ovary Cells by Cyclosporin A and Its Analogues¹

Departments of Obstetrics and Gynecology [S. K. C.], Medicine [W. N. H.], Pharmacology [S. R. K., R. E. H.], and Therapeutic Radiology [B. M. K.], Yale University School of Medicine, New Haven, Connecticut 06510-8063

Cyclosporins have been shown to sensitize multidrug-resistant cells to chemotherapeutic agents but, generally, have minimal effect on sensitive lines. We studied the effect of cyclosporin A (CsA) and two nonimmunosuppressive analogues, 11-methyl-leucine- (11-Me-Leu-CsA) and 6-methyl-alanine-cyclosporin A (6-Me-Ala-CsA), on the action of doxorubicin (DOX) and 4'-epidoxorubicin against parent (AuXB₁) and multidrug-resistant (CH^RC₅) Chinese hamster ovary cells. CsA and its two analogues reduced the IC₅₀ values for DOX in sensitive AuXB₁ cells from 0.1 to 0.01–0.02 µM. Cyclosporins reduced the IC₅₀ of DOX in resistant CH^RC₅ cells from 9 to 0.1 (CsA), 0.7 (6-Me-Ala-CsA), and 1.2 µM (11-Me-Leu-CsA). Similar results were seen when cyclosporins were combined with 4'-epidoxorubicin. The cyclosporins alone had no effect at these concentrations (1–2.0 µg/ml). Dose-response curves suggested that CsA was a more potent modifying agent than 11-Me-Leu-CsA towards resistant CH^RC₅ cells.

The ability of the cyclosporins to enhance anthracycline growth inhibition in parent AuXB₁ cells may be related to an increase in drug uptake and an increase in anthracycline-induced DNA damage. CsA increased DOX accumulation as well as DOX-associated DNA single-strand breaks in AuXB₁ cells over those seen in cells exposed to DOX alone. The degree of increase in DNA breaks paralleled the degree of growth inhibition seen in cells exposed to the same concentrations of drugs. In contrast, CsA had no effect on DOX accumulation or DNA single-strand breaks in CH^RC₅ cells. These findings imply that, in the resistant cell line, the enhanced anthracycline growth inhibition in the presence of CsA is independent of DOX accumulation and single-strand DNA breaks.

These studies demonstrate that CsA and two nonimmunosuppressive analogues can sensitize both sensitive and resistant Chinese hamster ovary cells to anthracyclines. Furthermore, the mechanisms underlying this effect may differ between sensitive and multidrug-resistant cells.

¹ Supported by a Yale University Comprehensive Cancer Center Collaborative Research Award 1987–1988 to S. K. C., ACS CH-67 to R. E. H., and NIH CA 43888 and ACS CH-453 to W. N. H. W. N. H. is a Burroughs-Wellcome Scholar in Clinical Pharmacology. A preliminary report of these data was presented at the 1988 American Association for Cancer Research meeting (1).

² To whom reprint requests should be addressed, at Department of Obstetrics and Gynecology, Yale University School of Medicine, 333 Cedar St., P. O. Box 3333, New Haven, CT 06510-8063.

Received 2/ 9/89. Revised 6/15/89. Accepted 8/14/89.