Reversal of Multidrug Resistance by Novel Nitrophenyl Pyrones, SNF4435C and D

SNF4435C and D, novel immunosuppressants produced by a strain of Streptomyces spectabilis, were examined for their reversing effects in vitro on various multidrug‐resistant (MDR) tumor cells overexpressing P‐glycoprotein. These two compounds in the range of 3–10 [jM completely reversed the resistance of MDR variant cells, mouse leukemia P388 cells [vincristine (VCR)‐resistant P388/ VCR and adriamycin (ADM)‐resistant P388/ADM], human myelogenous leukemia K562 cells (VCR‐resistant K562/VCR and ADM‐resistant K562/ADM) and human ovarian cancer A2780 cells (ADM‐resistant AD10), against VCR. Both compounds moderately potentiated the sensitivity of the MDR cells to ADM but the reversal was not complete. SNF4435C and D significantly increased the intracellular accumulation of VCR in AD10 cells as potently as verapamil, cyclosporin A (CysA) and FK506, whereas the compounds exerted no effect on the accumulation of VCR in the drug‐sensitive parent cells. Moreover, SNF4435C unproved the chemotherapeutic efficacy of VCR in the treatment of P388/VCR‐bearing mice. When 10 mg/kg SNF4435C was administered intra‐peritoneally to the mice concurrently with 0.2 mg/kg VCR for every 5 days, a treated/control (T/C) value of 143% was obtained. These results suggest that the compounds are useful candidates or tools for MDR modification in cancer chemotherapy.

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