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Mechanisms and modulation of multidrug resistance in primary human renal cell carcinoma
G H Mickisch1, K Roehrich, J Koessig
1Department of Urology, Mannheim Hospital, University of Heidelberg, Federal Republic of Germany.
Abstract:
Human renal cell carcinomas show a high degree of intrinsic multidrug resistance. In experimental cell lines, the membrane bound P-170 glycoprotein and the glutathione redox cycle seem to contribute to this phenomenon. P-170 may be inactivated by calcium antagonists; the glutathione redox cycle by buthionine sulfoximine. We studied the resistance patterns of 35 human renal cell carcinomas against vinblastine, doxorubicin and carboplatinum in a tetrazolium-based microculture assay. Concomitantly, P-170 expression was traced immunohistochemically using moab C219 and the glutathione content was determined enzymatically. Reversal of multidrug resistance was examined by applying the R-stereoisomer of verapamil and/or by addition of buthionine sulfoximine. A high degree of chemoresistance was seen in 27 tumors against vinblastine, in 30 tumors against doxorubicin and in 31 tumors against carboplatinum. Chemoresponse was found in eight, five or four cases respectively. P-170 was detected in 70% of highly vinblastine resistant and in 63% of highly doxorubicin resistant tumors, but in none of the less resistant cases. Resistance against carboplatinum and doxorubicin was significantly associated with elevated glutathione levels as compared to less resistant renal cell carcinomas. R-verapamil lead to a strong reversal of vinblastine resistance and to a distinct circumvention of doxorubicin resistance, but revealed no effect in carboplatinum resistance. Buthionine sulfoximine overcame carboplatinum resistance and modified doxorubicin resistance, but had no influence on vinblastine resistance. The combined application of R-verapamil and buthionine sulfoximine reversed doxorubicin resistance but did not act synergistically in vinblastine or carboplatinum resistance. Both mechanisms, P-170 and glutathione, occurred independently of each other and may well explain multidrug resistance of human renal cell carcinomas.
Insights
Human renal cell carcinomas exhibit significant multidrug resistance, often linked to P-170 glycoprotein and glutathione. Targeting these mechanisms with drugs like verapamil and buthionine sulfoximine shows potential for overcoming resistance in cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Human renal cell carcinomas (RCC) display intrinsic multidrug resistance (MDR).
- P-170 glycoprotein and the glutathione redox cycle are implicated in RCC MDR.
- Existing strategies aim to overcome MDR using agents like calcium antagonists and buthionine sulfoximine.
Purpose of the Study:
- To investigate resistance patterns in human RCC against common chemotherapeutics.
- To evaluate the roles of P-170 glycoprotein and glutathione in RCC chemoresistance.
- To assess the efficacy of R-verapamil and buthionine sulfoximine in reversing MDR in RCC.
Main Methods:
- A microculture assay was used to test resistance of 35 RCCs to vinblastine, doxorubicin, and carboplatinum.
- Immunohistochemistry (moab C219) and enzymatic assays quantified P-170 expression and glutathione levels.
- Reversal of MDR was studied using R-verapamil and/or buthionine sulfoximine.
Main Results:
- High chemoresistance was observed in most RCCs against the tested drugs.
- P-170 expression correlated with resistance to vinblastine and doxorubicin.
- Elevated glutathione levels were associated with resistance to carboplatinum and doxorubicin.
- R-verapamil reversed vinblastine and doxorubicin resistance; buthionine sulfoximine overcame carboplatinum resistance.
- Combined therapy showed synergistic effects only for doxorubicin resistance.
Conclusions:
- P-170 glycoprotein and glutathione are key independent mechanisms contributing to MDR in human RCC.
- Targeting these pathways offers potential therapeutic strategies for overcoming chemoresistance in renal cancer.
- Differential drug resistance and response to modulators highlight the complexity of MDR in RCC.