In vitro reversal of glutathione-S-transferase-mediated resistance in canine osteosarcoma (COS31) cells.
BACKGROUND
In this report we describe the establishment, characterization, and research utility of a cell line derived from a dog having a spontaneously occurring osteosarcoma (COS) made resistant to the cytotoxic effects of cisplatin chemotherapy.


METHODS
Established cells from passage 31 (COS31) were exposed to increasing sublethal concentrations of cisplatin in vitro.


RESULTS
A 2.2-fold increase in glutathione-S-transferase (GST) activity was found to be induced in this cell line (COS31/rCDDP) compared to parent cells. Furthermore, these cells were 7.8-fold more resistant to the cytotoxic effects of higher concentrations of cisplatin compared to parent cells. Ethacrynic acid was found to inhibit GST enzymatic activity and increase cisplatin cytotoxicity in resistant COS31 (COS31/rCDDP) cells.


CONCLUSIONS
Inhibiting the function of GST with ethacrynic acid pretreatment in humans and dogs with osteosarcoma may result in more tumor cells than normal cells killed in vivo by cisplatin, thus significantly prolonging lifespan without increasing host toxicity.
Shoieb
A M
AM
Department of Comparative Medicine, College of Veterinary Medicine, University of Tennessee, Knoxville 37901, USA.
Hahn
K A
KA
Van Laack
R L
RL
Barnhill
M A
MA
D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000662:veterinary*; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004283:Dog Diseases / Q000188:drug therapy* / Q000201:enzymology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004976:Ethacrynic Acid / Q000494:pharmacology*; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D012516:Osteosarcoma / Q000188:drug therapy / Q000201:enzymology / Q000662:veterinary*; D014407:Tumor Cells, Cultured
D005982:Glutathione Transferase; D004976:Ethacrynic Acid; D002945:Cisplatin