Radiosensitizing and toxic properties of quinoline and nitroquinoline complexes of platinum [PtCl2(NH3)quinoline].
The assessment of drugs designed to be useful in the eradication of hypoxic (resistant) cells involves comparison of hypoxic and aerobic radiosensitization, cytotoxicities, as well as DNA binding and reduction potentials. Three pairs of isomers of quinoline complexes [amino dichloro quinoline platinum (II)] were studied in this context. For the cis 5- and 6-nitroquinoline complexes, the DNA binding and toxicity were higher with the 5-substituted ligand. Reduction potentials were similar (-260 and -280 mV). No selectivity for hypoxic toxicity was observed, but radiosensitizing ability by both complexes was greater in hypoxic (than oxic) Chinese hamster ovary (CHO) cells. The trans 5-nitroquinoline complex produced better sensitization in hypoxia than its cis isomer [enhancement ratio (ER) 1.7 at 10 microM versus 40 microM for cis]. However, this was accompanied by some aerobic sensitization. The trans isomer of the (unsubstituted) quinoline complex was considerably more toxic than its cis isomer. Neither showed selectivity for hypoxia, either as radiosensitizers or as cytotoxins, which may be attributable to the lack of a reducible (nitro) function. Four quinoline complexes showed high activity in cisplatin-resistant L1210 cells, with the lowest resistance factor being for the trans quinoline complex. Results suggest that trans complexes with one aromatic ring may have activity different from the cis geometry, which should be exploited with respect to cisplatin resistance and cross-resistance with radiation.
Skov
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Medical Biophysics Department, B.C. Cancer Research Centre, Vancouver, Canada.
Adomat
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Doedee
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Farrell
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D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D016466:CHO Cells; D015687:Cell Hypoxia / Q000502:physiology; D002945:Cisplatin / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D004247:DNA / Q000378:metabolism; D007536:Isomerism; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D009600:Nitroquinolines / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D011804:Quinolines / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D011838:Radiation-Sensitizing Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D009600:Nitroquinolines; D009944:Organoplatinum Compounds; D011804:Quinolines; D011838:Radiation-Sensitizing Agents; D004247:DNA; D002945:Cisplatin