Enhancement of antitumor activity of mitomycin C in vitro and in vivo by UCN-01, a selective inhibitor of protein kinase C.
UCN-01 (7-hydroxy-staurosporine) is a potent and selective inhibitor of protein kinase C (PKC), one of several protein kinases examined. UCN-01 itself was shown to exhibit antitumor activity in vitro and in vivo in oncogene-activated human and murine tumor cell lines. Since the mechanism(s) of action of UCN-01 is thought to be different from those of alkylating agents, including mitomycin C (MMC), we tested the combined effect of UCN-01 with MMC on human epidermoid carcinoma A431 cells. UCN-01 potentiated the antiproliferative activity of MMC and yet it did not affect the growth of the cells in vitro. However, other nonselective protein kinase inhibitors, such as staurosporine, K-252a, KT6124 (a derivative of K-252a) and H7, did not enhance the activity of MMC. Isobologram analysis revealed that the interaction of UCN-01 with MMC was synergistic in its antiproliferative activity. A DNA histogram of A431 cells treated with both UCN-01 and MMC showed a block in the cell cycle at the G1/S phase. However, a histogram of cells treated with UCN-01 or MMC alone showed a G1 or a G2M block, respectively. The combined effect of UCN-01 with MMC was further examined in vivo in xenografted A431 cells in nude mice. The combination of both drugs in a single i.v. injection exhibited greater antitumor activity than MMC and UCN-01 alone (P < 0.01). This synergistic antitumor effect was also confirmed in two other solid tumor cell lines, i.e. human xenografted colon carcinoma Co-3 and murine sarcoma 180. The same was observed in the i.v.-inoculated P388 leukemia model, in which we saw an increased lifespan of mice when UCN-01 was combined with MMC. These results suggests the feasibility of using UCN-01 in clinical oncology, especially in combination with alkylating agents such as MMC. In addition, this combination therapy might be a novel chemotherapeutic approach to MMC-insensitive tumors in clinical trials.
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co. Ltd., Shizuoka-ken, Japan.
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Akinaga
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Nomura
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Gomi
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Okabe
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004357:Drug Synergism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D016685:Mitomycin / Q000494:pharmacology*; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D019311:Staurosporine / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured
D000470:Alkaloids; D016685:Mitomycin; C054852:7-hydroxystaurosporine; D011493:Protein Kinase C; D019311:Staurosporine