Chemotherapy has played a significant role in the improved survival rates observed in several human malignancies. Doxorubicin (DOX), bleomycin (BLM) and cisplatin (DDP) cause irreversible dose limiting damage to the heart, lung and kidney, respectively. The overall goal of this grant proposal is to decrease or, hopefully, eliminate these toxicities using specific experimental approaches designed for each drug (or drug class) listed above. 1) We have developed in vitro model of DOX induced cardiomyopathy using fetal mouse heart organ cultures that us to screen large numbers of compounds as well as to investigate direct drug effects on biochemical and pharmacological indices of cardiac function and damage. Better understanding of the biochemical mechanisms of DOX toxicity will enable us to develop pharmacological means of intervention-- either through analog development or use of of cardiac protective agents. 2) The mechanism of DDP induced nephrotoxicity is not understood. It has shown by us and others that it is possible to develop second and third generation platinum analogs with diminished nephrotoxic potential. We will investigate specific biochemical properties of a series of new platinum complexes apparently free of renal toxicity. This knowledge will aid in the clinical development of this highly promising series of new platinum complexes as well as aid in our understanding of heavy metal induced nephrotoxicity. 3) BLM induced pulmonary fibrosis appears to be an end result of drug induced acute lung inflammation. Using pharmacological and immunological approaches we will study the cellular and molecular changes that occur during this disease process. Such knowledge will allow us to design specific means of attenuating the extent of acute lung damage and thus diminish the severity of end stage fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Modified Research Career Development Award (K04)
Project #
5K04CA001205-04
Application #
3071752
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1987-09-30
Project End
1992-09-29
Budget Start
1990-09-30
Budget End
1991-09-29
Support Year
4
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Vermont & St Agric College
Department
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
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Dubowitz, H; Black, M (1991) Teaching pediatric residents about child maltreatment. J Dev Behav Pediatr 12:305-7
Farrell, N; Roberts, J D; Hacker, M P (1991) Shikimic acid complexes of platinum. Preparation, reactivity, and antitumor activity of (R,R-1,2-diaminocyclohexane) bis(shikimato) platinum(II). Evidence for a novel rearrangement involving platinum-carbon bond formation. J Inorg Biochem 42:237-46
Huot, A E; Hacker, M P (1990) Role of reactive nitrogen intermediate production in alveolar macrophage-mediated cytostatic activity induced by bleomycin lung damage in rats. Cancer Res 50:7863-6
Farrell, N; Qu, Y; Hacker, M P (1990) Cytotoxicity and antitumor activity of bis(platinum) complexes. A novel class of platinum complexes active in cell lines resistant to both cisplatin and 1,2-diaminocyclohexane complexes. J Med Chem 33:2179-84
Huot, A E; Gundel, R M; Hacker, M P (1990) Effect of erythrocytes on alveolar macrophage cytostatic activity induced by bleomycin lung damage in rats. Cancer Res 50:2351-5
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Janick-Buckner, D; Ranges, G E; Hacker, M P (1989) Alteration of bronchoalveolar lavage cell populations following bleomycin treatment in mice. Toxicol Appl Pharmacol 100:465-73
Hacker, M P; Lazo, J S; Pritsos, C A et al. (1989) Immobilized adriamycin: toxic potential in vivo and in vitro. Sel Cancer Ther 5:67-72