Reversal of multidrug resistance by novel nitrophenyl pyrones, SNF4435C and D.

Abstract

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.

• Authors: K Kurosawa, K Takahashi, E Tsuda, A Tomida, T Tsuruo
• Journal: Japanese journal of cancer research : Gann (Jpn J Cancer Res) Vol. 92 Issue 11 Pg. 1235-41 (Nov 2001) ISSN: 0910-5050 [Print] Japan
• PMID: 11714449 (Publication Type: Journal Article)

Chemical References

• Mitomycins
• Nitro Compounds
• Pyrones
• SNF 4435C
• SNF 4435D
• Vincristine
• Doxorubicin
• Mitolactol

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Cell Division (drug effects)
• Dose-Response Relationship, Drug
• Doxorubicin (pharmacology, therapeutic use)
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm
• Drug Synergism
• Female
• Humans
• Inhibitory Concentration 50
• Mice
• Mitolactol (pharmacology, therapeutic use)
• Mitomycins (pharmacology, therapeutic use)
• Neoplasm Transplantation
• Neoplasms (drug therapy)
• Nitro Compounds (pharmacology)
• Pyrones (pharmacology)
• Tumor Cells, Cultured
• Vincristine (pharmacology, therapeutic use)