Pharmacological basis for a novel therapeutic strategy based on the use of aquated cisplatin.
In pursuit of a strategy for increasing delivery of platinum drugs to tumors, we compared the cytotoxicity, extent of cellular uptake, and DNA platination of native cisplatin (DDP) and aquated cisplatin (aqDDP) in human head and neck carcinoma UMSCC10b cells. AqDDP was 1. 8-fold more toxic than DDP when tested against UMSCC10b cells in vitro. At high concentrations, aqDDP uptake was 3-fold more rapid than that of DDP; uptake of DDP and aqDDP was nonsaturable up to a concentration of 1600 micrometer. AqDDP produced 6.4-fold more platination of DNA than did DDP at the same concentration, suggesting that once inside the cell, aqDDP was 2-fold more effective at producing adducts in DNA than the native drug. Despite the paradox that aqDDP, which contains some charged species, entered the cell more rapidly than did neutral native DDP at high concentrations, studies on the effect of temperature, ATP depletion, and sulfhydryl group blockade did not provide evidence for uptake of aqDDP via a channel or transporter. AqDDP was more nephrotoxic to mice than DDP; however, s.c. administration of sodium thiosulfate protected against this toxicity and permitted a 7-fold escalation of aqDDP dose. These studies provide the preclinical basis for a novel therapeutic strategy based on the regional intraarterial or intracavitary administration of aqDDP in combination with a systemic neutralizing agent.
Zheng
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Department of Medicine and the Cancer Center, University of California at San Diego, La Jolla, California 92093-0058, USA.
Fink
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Howell
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D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D002294:Carcinoma, Squamous Cell; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000633:toxicity*; D006258:Head and Neck Neoplasms; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007700:Kinetics; D051379:Mice; D013696:Temperature; D014407:Tumor Cells, Cultured
C034297:diamminediaqua platinum(II); D000255:Adenosine Triphosphate; D002945:Cisplatin