Kinetics and mechanism of the 1-beta-D-arabinofuranosylcytosine-induced potentiation of cis-diamminedichloroplatinum(II) cytotoxicity.
Certain aspects of the potentiation induced by 1-beta-D-arabinofuranosylcytosine (ara-C) on cis-diamminedichloroplatinum(II) (cis-DDP) cytotoxicity were investigated. The time dependency of additions of ara-C and cis-DDP was established by allowing cells to grow for various intervals in fresh medium following the removal of one agent before adding the second one. ara-C had no potentiating effect on cis-DDP toxicity when given to the cells before the addition of cis-DDP. When the experiment was reversed so that cis-DDP was added first and ara-C second, a slight potentiating effect was observed even if the drugs were added 4 h apart. The optimal toxic effect was obtained when ara-C and cis-DDP were added together. Continuous exposure of cells to concentrations of ara-C and cis-DDP 10 times lower than those used in pulse treatment experiments resulted in an additive rather than a synergistic effect. ara-C, unable to kill cells in pulse treatment, killed 96% of the cells after 24 h of continuous incubation. Thiourea was able to prevent the cytotoxic effect of cis-DDP in a concentration-dependent manner when given to the cells immediately following their treatment with cis-DDP; at 0.1 M thiourea, the cytotoxic effect of cis-DDP was almost completely prevented. Similar results were obtained when the cells were exposed to a combination of cis-DDP and ara-C. In this case, 0.1 M thiourea resulted in over 80% survival of cells treated with the drug combination. Thiourea had to be added to the cells either together with cis-DDP or immediately following removal of the drug in order to completely prevent the cytotoxic effect. A similar time factor was involved when cells were treated with a combination of cis-DDP and ara-C before their exposure to thiourea, but in this case thiourea was only able to prevent completely the cytotoxic effect when added simultaneously with the drug combination. In other experiments, the effect of thiourea on cis-DDP-induced DNA cross-linking was measured by the alkaline elution technique. Thiourea was capable of preventing DNA cross-link formation both in cells treated with cis-DDP alone, and in cells exposed to the combination of cis-DDP and ara-C These observations further support the contention that ara-C potentiates cis-DDP cytotoxicity by increasing the ability of the platinum compound to form earlier, more stable DNA cross-links regardless of whether it is present in free or monoadducted form.(ABSTRACT TRUNCATED AT 400 WORDS)
Vadi
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Drewinko
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D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002474:Cell-Free System; D002945:Cisplatin / Q000008:administration & dosage*; D003110:Colonic Neoplasms / Q000188:drug therapy; D003432:Cross-Linking Reagents; D003561:Cytarabine / Q000008:administration & dosage*; D004247:DNA / Q000378:metabolism; D004273:DNA, Neoplasm / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004357:Drug Synergism; D006801:Humans; D007700:Kinetics; D013890:Thiourea / Q000008:administration & dosage
D003432:Cross-Linking Reagents; D004273:DNA, Neoplasm; D003561:Cytarabine; D004247:DNA; D013890:Thiourea; D002945:Cisplatin