Effects of Buthionine Sulfoximine Mediated Glutathione Depletion in Chemoresistant Human Renal Cell Carcinomas
Defined resistance factors play a substantial role in the characterization of chemoresistance. Glutathione metabolism is apparently involved in the expression of high chemoresistance in human renal cell carcinoma. In 35 renal cell carcinomas, primary monolayer cultures were generated, the glutathione content enzymatically determined, and depletion of glutathione instigated by buthionine sulfoximine, a specific inhibitor of glutathione biosynthesis, was studied. Furthermore, the degree of chemoresistance against doxorubicin and carboplatin was determined in an MTT microculture assay and the possibility of modulation of resistance by buthionine sulfoximine was examined.
The glutathione content amounted to 81 ±26 nM/mg protein. A high degree of chemoresistance waa associated with increased levels, a low degree with reduced levels. With appropriate culture conditions, the glutathione content could be reduced to approximately 30% of the control value. Thus, a distinct potentiation of carboplatin cytotoxicity could be detected and doxorubicin resistance was still measurably subdued.
KeywordsOncol Doxorubicin Melphalan Cyclophosphamide Myeloma
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- Hamilton TC, Winker MA, Louie KG, Batist G, Behrens BC, Tsuruo T, Grotzinger KR, McKoy WK, Young RC, Ozols RF (1985) Augmentation of adriamycin, melphalan, and cisplatin cytotoxicity in drug-resistant and sensitive human ovarian carcinoma cell lines by sulfoximine mediated glutathione depletion. Biochem Pharmacol 34:2583–2586.PubMedCrossRefGoogle Scholar
- Holm S (1979) A simple sequentially rejective multiple test procedure. Scand J Statist 6:65–70.Google Scholar
- Ono K, Shrieve DC (1987) Effect of glutathione depletion by L-buthionine sulf-oximine on the cytotoxicity of cyclophosphamide in single and fractionated doses to EMT6/SF mouse tumors and bone marrow. J Natl Canc Inst 79:811–815.Google Scholar
- Page JG, Carlton BD, Smith AC, Kastello MD, Grieshaber CK (1987) Preclinical toxicology and pharmacokinetic studies of buthionine sulfoximine (BSO, NSC-326231) in CD2F1 mice. Proc AACR 28:440.Google Scholar
- Shea TC, Kelly SL, Henner WD (1987) Identification of an anionic form of glutathione transferase present in many human tumors and human tumor cell lines. Cancer Res 48:527–533.Google Scholar
- Smith AC, Page JG, Carlton BD, Kastello MD, Grieshaber CK (1987) Preclinical toxicology and pharmacokinetic studies of buthionine sulfoximine (BSO, NSC-326231) in beagle dogs. Proc AACR 28:440.Google Scholar
- Tomashewsky P, Astor M, White R (1985) Relationship between thiol depletion and chemosensitization in a transplantable murine bladder tumor. J Natl Cancer Inst 74:1233–1238.Google Scholar
- Torti FM (1983) Treatment of metastatic renal cell carcinoma. In: Torti FM (ed) Urologic cancer: chemotherapeutic principles and management. Springer, Berlin Heidelberg New York Tokyo, pp 85, 123–143.Google Scholar