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 (CHRC5) 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 microM. Cyclosporins reduced the IC50 of DOX in resistant CHRC5 cells from 9 to 0.1 (CsA), 0.7 (6-Me-Ala-CsA), and 1.2 microM (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 micrograms/ml). Dose-response curves suggested that CsA was a more potent modifying agent than 11-Me-Leu-CsA towards resistant CHRC5 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 CHRC5 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.