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Cross-resistance patterns related to glutathione metabolism in primary human renal cell carcinoma
1Department of Urology, Mannheim Hospital, University of Heidelberg, FRG.
Abstract:
In 59 cases of primary human renal cell carcinoma (RCC), cross-resistance and collateral susceptibility patterns were determined in an MTT microculture assay. Concomitantly, the glutathione (GSH) content and the enzymatic activity of gamma-glutamyl transpeptidase (GGT) were measured as distinct resistance characteristics. Resistance or chemoresponse towards Vinca alkaloids and anthracyclines were found to be highly coincident, suggesting that the classical multidrug resistance mechanism is active in human RCC. Strong resistance to platinum complexes combined with relative sensitivity to bleomycin was significantly associated with elevated glutathione levels, providing evidence for another pathway instigating chemoresistance. In contrast, despite substantial enzymatic activity, GGT effects revealed no correlation to the chemoresistance pattern. This result implies that it is the GSH-linked binding and reduction potential rather than the GGT-associated transportation capacity that has an impact on the expression of chemoresistance in human RCC.
Insights
Multidrug resistance is active in human renal cell carcinoma (RCC). Elevated glutathione levels, not GGT activity, correlate with chemoresistance patterns, impacting treatment strategies for kidney cancer.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Renal cell carcinoma (RCC) exhibits complex chemoresistance.
- Understanding resistance mechanisms is crucial for effective cancer therapy.
Purpose of the Study:
- To investigate cross-resistance and collateral susceptibility patterns in human RCC.
- To evaluate the roles of glutathione (GSH) and gamma-glutamyl transpeptidase (GGT) in chemoresistance.
Main Methods:
- MTT microculture assay used on 59 primary human RCC cases.
- Measurement of cellular glutathione content.
- Assay of gamma-glutamyl transpeptidase enzymatic activity.
Main Results:
- Coincident resistance to Vinca alkaloids and anthracyclines suggests classical multidrug resistance.
- Elevated GSH levels correlated with resistance to platinum complexes and sensitivity to bleomycin.
- GGT activity showed no correlation with chemoresistance patterns in RCC.
Conclusions:
- Classical multidrug resistance mechanisms are active in human RCC.
- Glutathione's role in binding and reduction potential significantly impacts chemoresistance.
- GGT activity does not appear to be a major determinant of chemoresistance in this context.