IN-VITRO AND IN-VIVO REVERSAL OF CANCER CELL MULTIDRUG-RESISTANCE BY THE SEMISYNTHETIC ANTIBIOTIC TIAMULIN

A large number of multidrug resistance (MDR) modulators, termed chemos ensitizers, have been identified from a variety of chemicals, but most have been proven to be clinically toxic. Low concentrations of the pl euromutilin-derived semi-synthetic antibiotic tiamulin (0.1 to 10 mu M ) sensitized the three highly resistant P-glycoprotein (Pgp)-overexpre ssing tumor cell lines P388 (murine lymphoid leukemia), AS30-D (rat he patoma), CEM (human lymphoblastic leukemia), and the barely resistant AS30-D/S cell lines to several MDR-related anticancer drugs. Flow cyto metric analysis showed that tiamulin significantly increased the intra cellular accumulation of daunomycin. When compared to reference modula ting agents such as verapamil and cyclosporin A, tiamulin proved to be 1.1 to 8.3 times more efficient in sensitizing the resistant cell lin es. Moreover, when given i.p. (1.6 mu g/mg body weight), tiamulin incr eased the survival rate of adriamycin treated mice bearing the P388/AD R25 tumor line by 29%. In the presence of an anticancer drug, tiamulin inhibited both ATPase and drug transport activities of Pgp in plasma membranes from tumor cells. Tiamulin is thus a potent chemosensitizer that antagonizes the Pgp-mediated chemoresistance in many tumor cell l ines expressing the MDR phenotype at different levels and displays no toxic effects on contractile tissues at active doses, therefore provid ing the promise for potential clinical applications. (C) 1998 Elsevier Science Inc.