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 microM 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 AD(10)), 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 AD(10) 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 improved the chemotherapeutic efficacy of VCR in the treatment of P388/VCR-bearing mice. When 10 mg/kg SNF4435C was administered intraperitoneally 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.
Kurosawa
K
K
Research Institute of Life Science, Snow Brand Milk Products Co., Ltd., Ishibashi-machi, Shimotsuga-gun, Tochigi 329-0512. kurosawa9630@nifty.com
Takahashi
K
K
Tsuda
E
E
Tomida
A
A
Tsuruo
T
T
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008936:Mitolactol / Q000494:pharmacology / Q000627:therapeutic use; D008937:Mitomycins / Q000494:pharmacology / Q000627:therapeutic use; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy; D009574:Nitro Compounds / Q000494:pharmacology*; D011753:Pyrones / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology / Q000627:therapeutic use
D008937:Mitomycins; D009574:Nitro Compounds; D011753:Pyrones; C435067:SNF 4435C; C435066:SNF 4435D; D014750:Vincristine; D004317:Doxorubicin; D008936:Mitolactol