A study of ethacrynic acid as a potential modifier of melphalan and cisplatin sensitivity in human lung cancer parental and drug-resistant cell lines.
We have studied alterations in glutathione (GSH) levels and glutathione-S-transferase (GST) activity in a series of in vitro derived multidrug resistant and cisplatin resistant sublines of the human lung cancer lines NCI-H69 (small cell), COR-L23 (large cell) and MOR (adenocarcinoma). We have also investigated the effects of ethacrynic acid, a putative inhibitor of GSTs, on levels of GSH and GST activity and on cellular sensitivity to melphalan and to cisplatin. Neither GSH content nor GST activity were significantly greater in the resistant sublines compared with their respective parental lines. The only effects of treating with ethacrynic acid at doses of 1 microgram ml-1 and 3 micrograms ml-1 for 2 h were a reduction in GSH content in the cisplatin resistant subline H69/CPR at the 3 micrograms ml-1 dose, and an increase to over 140% of control at 1 microgram ml-1 and 3 micrograms ml-1 in the MOR parental line (MOR/P) and at 1 microgram ml-1 in the multidrug resistant subline MOR/R. Exposure of parental line COR-L23/P to 3 micrograms ml-1 and 6 micrograms ml-1 of ethacrynic acid for 24 h, however, increased the GSH content to over 300% and 500% of control respectively. Variable effects of ethacrynic acid on GST activity were seen in these cell lines. Doses of 1 microgram ml-1 and 3 micrograms ml-1 reduced activity to 59% and 48% of control respectively in multidrug resistant subline H69/LX4. On the other hand, activity was increased in the cisplatin resistant subline H69/CPR (to 146% and 218% of control) and in MOR/P (to 117% and 137% of control) by 1 microgram ml-1 and 3 micrograms ml-1 respectively of ethacrynic acid. Addition of ethacrynic acid (3 micrograms ml-1) to treatment of the cell lines with melphalan or with cisplatin did not alter the dose-response curves to these agents.
Rhodes
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MRC Clinical Oncology and Radiotherapeutics Unit, Medical Research Council Centre, Cambridge, UK.
Twentyman
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PR
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage; D004347:Drug Interactions; D004351:Drug Resistance / Q000502:physiology; D004354:Drug Screening Assays, Antitumor; D004976:Ethacrynic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism / Q000494:pharmacology; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008558:Melphalan / Q000008:administration & dosage; D014407:Tumor Cells, Cultured / Q000187:drug effects
D005982:Glutathione Transferase; D005978:Glutathione; D004976:Ethacrynic Acid; D002945:Cisplatin; D008558:Melphalan