Cis-platinum is a highly effective and widely used anticancer drug; severe toxicity, particulary to the kidney and gastrointestinal tract, limits both the dose and duration of chemotherapy with this promising drug. We have demonstrated that diethyldithiocarbamate (DDTC) protects against cis-platinum toxicity to the kidney, GI tract, and bone marrow in a variety of animal species, and it inhibits nausea and vomiting in the dog. These benefits are achieved without inhibiting the antitumor properties of the drug, and the protective effects of DDTC allow use of much higher doses of cis-platinum with impressive increases in tumor response. Phase I clinical trials are now underway. The long range objectives of the research outlined in this application are to increase our understanding of the interactions among platinum(II) complexes, the biological ligands with which they react, and the DDTC ligand, and to utilize this knowledge to optimize DDTC's efficacy as a clinical chemoprotective agent.
Specific aims i nclude 1) The utilization of pharmacokinetic data to optimize the therapeutic index of the DDP-DDTC combination; 2) Determination of the mechanism by which cis-platinum causes nephrotoxicity and the basis whereby delayed administration of DDTC protects against this toxicity; 3) Determination of the mechanism by which platinum drugs cause bone marrow toxicity, and evaluate the ability of DDTC to inhibit marrow toxicity induced by the platinum drugs and other cross-linking agents; 4) Determination of both the generality and the mechanistic basis for DDTC's ability to potentiate the anti-tumor activity of cis-platinum. Pharmacokinetics will be measured in Phase I patients and in rodents using our recently developed HPLC methods; mechanisms of renal toxicity will be studied using enzyme kinetics, electron microscopy, and low temperature solids nmr. Bone marrow experiments will be carried out in mice by direct measurement of marrow cellularity, assessment of CFU-S and CFU-C activity, and determination of DNA interstrand cross-linking by alkaline elution. The basis for DDTC potentiation will be investigated with platinum-nucleoside complexes as models to study their redox properties and their reactions with active oxygen species.
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