Enhancement of etoposide-induced cytotoxicity by cyclosporin A.
Following the clinical observation of enhanced antineoplastic action of etoposide in the presence of cyclosporin A (CyA), we investigated this drug interaction in several in vitro and in vivo tumor systems. Macromolecular DNA damage induced by etoposide at drug levels comparable to plasma AUC values achieved in patients was increased not only in leukemic peripheral blood cells from patients but also in mononuclear peripheral blood cells from a healthy donor. Intracellular retention of radioactivity from 3H-etoposide was increased by a factor of 1.5 at the most in the presence of CyA. The cytotoxicity of etoposide and adriamycin to L 1210 leukemic cells was clearly enhanced, whereas CyA had no effect on the action of cisplatin or ionizing irradiation. At CyA blood levels not exceeding 1.44 microgram/ml, increased tumor inhibition of etoposide was observed in a human embryonal cancer xenograft, but there was also higher lethality in normal mice. We conclude from our own data and from other recent findings that with respect to chemosensitization the effects of CyA resemble those of calcium channel blockers or anticalmodulin agents. In contrast to calcium channel blockers, however, adequate plasma levels of CyA can well be achieved in patients.
D000818:Animals; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology; D003524:Cyclosporins / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D004347:Drug Interactions; D005047:Etoposide / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007928:Lethal Dose 50; D007939:Leukemia L1210 / Q000188:drug therapy; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy; D011839:Radiation, Ionizing
D003524:Cyclosporins; D005047:Etoposide; D004317:Doxorubicin; D002945:Cisplatin