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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA034620-10
Application #
3172376
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1982-09-01
Project End
1995-02-28
Budget Start
1992-03-01
Budget End
1993-02-28
Support Year
10
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Rochester
Department
Type
Schools of Dentistry
DUNS #
208469486
City
Rochester
State
NY
Country
United States
Zip Code
14627
Kennedy, S M; Borch, R F (1999) IL-1beta mediates diethyldithiocarbamate-induced granulocyte colony-stimulating factor production and hematopoiesis. Exp Hematol 27:210-6
Patil, R R; Borch, R F (1995) Granulocyte-macrophage colony-stimulating factor expression by human fibroblasts is both upregulated and subsequently downregulated by interleukin-1. Blood 85:80-6
East, C J; Abboud, C N; Borch, R F (1992) Diethyldithiocarbamate induction of cytokine release in human long-term bone marrow cultures. Blood 80:1172-7
Montine, T J; Borch, R F (1990) Role of endogenous sulfur-containing nucleophiles in an in vitro model of cis-diamminedichloroplatinum(II)-induced nephrotoxicity. Biochem Pharmacol 39:1751-7
Schmalbach, T K; Borch, R F (1989) Diethyldithiocarbamate modulation of murine bone marrow toxicity induced by cis-diammine(cyclobutanedicarboxylato)platinum (II). Cancer Res 49:6629-33
Schmalbach, T K; Borch, R F (1989) Myeloprotective effect of diethyldithiocarbamate treatment following 1,3-bis(2-chloroethyl)-1-nitrosourea, adriamycin, or mitomycin C in mice. Cancer Res 49:2574-7
DeGregorio, M W; Gandara, D R; Holleran, W M et al. (1989) High-dose cisplatin with diethyldithiocarbamate (DDTC) rescue therapy: preliminary pharmacologic observations. Cancer Chemother Pharmacol 23:276-8
Gringeri, A; Keng, P C; Borch, R F (1988) Diethyldithiocarbamate inhibition of murine bone marrow toxicity caused by cis-diamminedichloroplatinum(II) or diammine-(1,1-cyclobutanedicarboxylato)platinum(II). Cancer Res 48:5708-12
Montine, T J; Borch, R F (1988) Quiescent LLC-PK1 cells as a model for cis-diamminedichloroplatinum(II) nephrotoxicity and modulation by thiol rescue agents. Cancer Res 48:6017-24
Dedon, P C; Borch, R F (1987) Characterization of the reactions of platinum antitumor agents with biologic and nonbiologic sulfur-containing nucleophiles. Biochem Pharmacol 36:1955-64

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