Toxicity of [PtCl2(NH3)L] in hypoxia; L = misonidazole or metronidazole.
There is increasing interest in compounds which show selective toxicity to the resistant hypoxic portions of tumors. Cisplatin does not generally show preferential toxicity in hypoxic cells, as do nitroimidazoles. It is proposed that attachment of a nitroimidazole could add a degree of hypoxic selectivity to Pt agents. Platinum complexes containing one nitroimidazole ligand bind to DNA and show higher toxicity in hypoxic than aerobic CHO cells. Cis and trans isomers of complexes with misonidazole (a 2-nitroimidazole) and metronidazole (a 5-nitroimidazole) are compared with respect to binding to DNA (approximately the same), reduction potential (trans miso greater than cis miso greater than cis metro greater than trans metro), and toxicity (trans greater than cis miso, cis greater than trans metro, with trans miso approximately cis metro in hypoxia, despite significantly different reduction potentials). The effect of platination on nitroimidazole toxicity is not entirely explained by DNA binding and increased reduction potential. These compounds do not exhibit cross resistance with cisplatin in L1210 resistant cells. This factor, their selectivity for hypoxia, and preliminary results in vivo indicating potentiation of anti-tumor activity by the vasoactive compound, hydralazine, which increases tumor hypoxia, suggest further development of these compounds for use in tumors with resistant hypoxic portions.
Skov
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Medical Biophysics Unit, BC Cancer Research Centre, Vancouver, Canada.
Adomat
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Chaplin
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Farrell
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D000332:Aerobiosis / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000138:chemical synthesis / Q000633:toxicity*; D015687:Cell Hypoxia / Q000187:drug effects*; D002945:Cisplatin / Q000138:chemical synthesis / Q000633:toxicity*; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004262:DNA Restriction Enzymes / Q000037:antagonists & inhibitors; D015195:Drug Design; D004351:Drug Resistance; D007939:Leukemia L1210 / Q000188:drug therapy / Q000378:metabolism; D008795:Metronidazole / Q000138:chemical synthesis / Q000633:toxicity*; D008920:Misonidazole / Q000138:chemical synthesis / Q000633:toxicity*; D010084:Oxidation-Reduction; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D008795:Metronidazole; D008920:Misonidazole; D004247:DNA; D004262:DNA Restriction Enzymes; D002945:Cisplatin