The goal of the proposed research is to examine the use of dithiocarbamate chelating agents (which we have recently prepared) in controlling the nephrotoxicity of cis-platinum at normal and elevated dosage levels. Renal function in experimental animals (rats) will be monitored (via measurement of serum creatinine levels and blood urea nitrogen values) as the animals are taken through various protocols designed to allow the administration of cis-platinum under conditions selected to produce minimum nephrotoxicity. These same protocols will be examined for anti-tumor efficacy in the rat using cis-platinum sensitive Walker 256 carcinosarcoma (ATCC)(CL38) to determine the effect of the measures used to reduce nephrotoxicity on the anti-cancer activity of the cis-platinum. Analogous studies will be carried out using other transplantable tumors in rats and mice (70). Dose-response curves will be developed to determine the effect of chelating agent dosage on the course of blood urea nitrogen levels, serum creatine values and platinum mobilization. The chelating agents which we plan to use are primarily ones which we have prepared and shown to be capable of reducing the nephrotoxicity of cis-platinum without altering the anti-cancer activity significantly, in the Walker 256 model system, though structurally related compounds will also be examined. Experimental determination of the effect of these chelating agents on the cytotoxicity of cis-platinum will also be carried out as preliminary results indicate that perhaps only part of the reduction in nephrotoxicity which has been observed is due to chelation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA038997-05
Application #
3177598
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1986-04-01
Project End
1991-03-31
Budget Start
1990-04-01
Budget End
1991-03-31
Support Year
5
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
Schools of Arts and Sciences
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Beaty, J A; Jones, M M; Ma, L (1992) The reactions of cis-[Pt(NH3)2(H2O)2]2+ with L-(+)-cystathionine and seleno-L-methionine: potential relevance to the molecular basis of cisplatin toxicity. Chem Res Toxicol 5:647-53
Jones, M M; Basinger, M A; Holscher, M A (1992) Control of the nephrotoxicity of cisplatin by clinically used sulfur-containing compounds. Fundam Appl Toxicol 18:181-8
Jones, M M; Basinger, M A; Holscher, M A (1991) Thioether suppression of cisplatin nephrotoxicity in the rat. Anticancer Res 11:449-53
Jones, M M; Basinger, M A; Holscher, M A (1991) Relative effectiveness of some compounds for the control of cisplatin-induced nephrotoxicity. Toxicology 68:227-47
Jones, M M; Basinger, M A; Field, L et al. (1991) Coadministration of dimethyl sulfoxide reduces cisplatin nephrotoxicity. Anticancer Res 11:1939-42
Jones, M M; Basinger, M A; Beaty, J A et al. (1991) The relative nephrotoxicity of cisplatin, cis-[Pt(NH3)2(guanosine)2]2+, and the hydrolysis product of cisplatin in the rat. Cancer Chemother Pharmacol 29:29-32
Jones, M M (1991) New developments in therapeutic chelating agents as antidotes for metal poisoning. Crit Rev Toxicol 21:209-33
Basinger, M A; Jones, M M; Holscher, M A (1990) L-methionine suppresses pathological sequelae of cis-platinum in the rat. Fundam Appl Toxicol 14:568-77
Basinger, M A; Jones, M M; Holscher, M A (1990) L-methionine antagonism of cis-platinum nephrotoxicity. Toxicol Appl Pharmacol 103:1-15
Jones, M M; Basinger, M A (1989) Control of nephrotoxicity in the rat during repeated cis-platinum treatments. J Appl Toxicol 9:229-33

Showing the most recent 10 out of 12 publications