Doctoral Dissertations

Date of Award

5-1998

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Comparative and Experimental Medicine

Major Professor

Kevin Hahn

Committee Members

Robert Hall, Donita Frazier, Erby Wilkinson

Abstract

Osteosarcoma is a highly malignant and rapidly fatal disease in dogs and humans. Since osteosarcoma in dogs and humans are virtually indistinguishable clinically and pathologically, the dogs has been used as an animal model. In this research, the long-range goal was to understand the role of the glutathione-S-transferases (GSTs) in clinical anticancer drug resistance. The hypothesis to be tested was that cisplatin resistance is mediated by the GSTs in osteosarcomas. The objectives of this research were to 1) determine if an in vivo relationship exists between the relative tumor concentration of GST π and response to cisplatin treatment in dogs with appendicular osteosarcoma, 2) establish canine osteosarcoma cells in culture and determine if cells retain similar biological and pathological properties in vitro and following implantation in nude mice, and 3) establish a canine osteosarcoma cell line resistant to the cytotoxic effects of cisplatin and determine if resistance is mediated by the GSTs and, if so, reversible upon the addition of ethacrynic acid. In this research, an increased expression of GST π in the primary tumors of a dog with osteosarcoma was related to a shorter remission and survival time. Furthermore, When canine osteosarcoma cells were established in culture, the cell line displayed all of the classical in vitro growth parameters of human osteosarcoma as well as the ability to produce tumors histologically typical of canine osteosarcoma when transplanted in athymic nude mice. Following prolonged exposure to increasing concentrations of cisplatin in vitro, a two-fold increase in and eight-fold increase in cisplatin resistance was observed. Complete reversal of cisplatin resistance occurred when the GST inhibitor; ethacrynic acid, was used. The cell lines created and evaluated in this research may exemplify the proper biologic and therapeutic model for studying cisplatin resistance mechanisms and innovative strategies to circumvent or delay its induction. From these results, it is anticipated that inhibiting the function of GST π with ethacrynic acid pretreatment in humans and dogs with osteosarcoma that more tumor cells than normal cells will be killed in vivo by cisplatin, thus significantly prolonging lifespan without increasing host toxicity.

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