MODULATION OF MULTIDRUG-RESISTANCE BY SDZ PSC-833 IN LEUKEMIC AND SOLID-TUMOR-BEARING MOUSE MODELS

P-Glycoprotein inhibitors, including the nonimmunosuppressive cyclospo rin D analog SDZ PSC 833 (PSC 833), have been developed to circumvent multidrug resistance, In the present study, the potential of PSC 833 i n reversing multidrug resistance was evaluated in various systemic tre atment models with leukemic and solid-tumor-bearing mice, Having a rel atively wide therapeutic window of daily p.o. doses from 12.5 to 75 mg /kg, PSC 833 significantly improved the antileukemic activity of the a nticancer drugs adriamycin (ADM), vincristine (VCR) and etoposide (VP- 16) given i.p. or i.v. against i.p.-inoculated vincristine-resistant P 388 tumor (P388/VCR), PSC 833 in combination with i.p.-injected antica ncer drugs in optimal schedule and dosage induced apparent cures in so me leukemic mice, whereas no cures were obtained with the cyclosporin A/anticancer drug combinations. PSC 833 combined with i.v.-injected an ticancer drugs was highly active, but not curative, against P388/VCR a nd parental P388 tumors (maximum T/C>175%), PSC 833 in combination wit h intravenous treatment with ADM showed prominent anti-solid-tumor act ivity against s.c.-inoculated colon adenocarcinoma 26 and human colore ctal adenocarcinoma HCT-15, Against colon adenocarcinoma 26, the PSC 8 33/ADM combinations induced cure in two or three of six mice, PSC 833/ ADM combinations significantly inhibited the growth of the tumor with maximum percent inhibitions of 83 and 73% in the early and advanced st ages of the HCT-15 tumor models, respectively, The present study demon strated that PSC 833 is highly active in potentiating the antitumor ac tivity of systemically administered ADM, VCR and VP-16 against four mu rine and human tumors with a relatively wide therapeutic window of dai ly p.o. dose range of 12.5-100 mg/kg.