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Oncopharmacology/Biotechnology Department, Preclinical Research, Sandoz Pharma A.G., Postfach CH 4002, Basel, Switzerland [D. B., C. G., B. J., P. B., F. L.], and Immunology Laboratory, Université Louis Pasteur, Strasbourg 1, BP 24, F 67401 Illkirch, France [D. B., A. P-M., F. L.]
The new nonimmunosuppressive cyclosporin analogue, SDZ PSC 833, is a very potent multidrug-resistance modifier. In vitro, it was shown to be at least 10-fold more active than cyclosporin A (Sandimmune), itself more active than verapamil, on most P-glycoprotein-expressing multidrug-resistant (MDR) tumor cell lines. In vivo, SDZ PSC 833 was tested in a few protocols of combined therapy with either Vinca alkaloids or doxorubicin as anticancer drugs, using the homologous tumor-host system (P388 cells of DBA/2 origin grafted into DBA/2 or B6D2F1 mice). Although these MDR-P388 tumor cells belong to a highly resistant variant that in vitro required about 150-fold more anticancer drug for 50% cell growth inhibition than the parental P388 cells, significant prolongation of survival times of the MDR-P388 tumor-bearing mice was obtained when treated with a combination of SDZ PSC 833 p.o. were otherwise ineffective doses of anticancer drugs given i.p. This chemosensitizing effect of SDZ PSC 833 was dose-dependent and was most effective in a protocol combining administration of SDZ PSC 833 p.o. 4 h before a doxorubicin i.p. injection: in comparison with the survival of MDR-P388 tumor-bearing mice treated with the anticancer drug alone, the pretreatment with SDZ PSC 833 at 25 and 50 mg/kg gave 2- to 3-fold increases of survival times. Since the MDR-P388 tumor cells used in our studies belong to a highly resistant variant, with a much higher degree of drug resistance than the one known to occur in cancer patients, SDZ PSC 833 appears to be a very promising chemosensitizer.
1 The part of this work performed at Strasbourg University was supported by grants from Sandoz, Basel.
2 Present address: Yale University, Department of Laboratory Medicine, School of Medicine, 333 Cedar Street, P. O. Box 3333, New Haven, CT 06310.
3 To whom requests for reprints should be addressed.
Received 1/23/91. Accepted 6/ 4/91.
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