Molecular Analysis of Mechanisms Regulating Drug Sensitivity and the Development of New Chemotherapy Strategies for Genitourinary Carcinomas

Abstract

The emergence of drug-resistant tumors during treatment remains one of the major obstacles in cancer chemotherapy. Overexpression of P-glycoprotein encoded by the multidrug resistance 1 (MDR1) gene or multidrug resistance-associated protein (MRP) (or both) and decreased expression of DNA topoisomerase II are responsible for expression of the multidrug resistance (MDR) phenotype. The expression of P-glycoprotein is also often observed in untreated cancers showing spontaneous MDR, such as renal cell carcinoma. Regarding cisplatin resistance, decreased cisplatin accumulation, an increase in cisplatin detoxification by glutathione-related enzymes or metallothionein (or both), and increased repair of DNA damage are all considered to play an important role. The combination of reversal agents targeting such drug resistance markers may be a way to improve the outcome of chemotherapy. Regarding the presently available reversal agents, however, clinically relevant chemosensitizing doses cannot be given to humans without inducing significant toxicity. The development of new agents that reverse drug resistance without causing significant toxicity and their clinical application based on the mechanisms regulating drug sensitivity may therefore be a potentially effective new treatment strategy for genitourinary carcinomas.

Ectonucleoside triphosphate diphosphohydrolase 6 expression in testis and testicular cancer and its implication in cisplatin resistance

“…cisplatin resistance is thought to be complex and multicausal phenomenon. Many resistance-related molecules including detoxifying enzymes, drug-efflux pumps, DnA repair enzymes and apoptosis-related genes have been reported (26,27). In this study, we identified that ENTPD6 may be a factor determining cisplatin sensitivity in testicular cancer.…”

Usefulness of Liposomes Loaded with Cytostatic Bile Acid Derivatives to Circumvent Chemotherapy Resistance of Enterohepatic Tumors

“…Because one of the major mechanisms of resistance is that mediated by export proteins, several inhibitors of these pumps have been investigated. However, clinically relevant chemosensitizing doses of the currently available reversal agents cannot be given to humans without significant side effects (Naito et al, 2000). An alternative to the functional blocking of exporting pumps is enhancing drug specificity toward tumor cells to reach intracellular concentrations of the active agent enough to carry out its cytostatic effect.…”

Generation of RAGE‐1 and MAGE‐9 peptide‐specific cytotoxic T‐Lymphocyte lines for transfer in patients with renal cell carcinoma

“…As >80% of RCCs express the phenotype of multidrug resistance, chemotherapy is rarely efficient. [4][5][6] However, RCCs are supposed to be immunogenic; 7-11 hence, immunotherapeutic strategies are dominant. should be mentioned.…”

“…As >80% of RCCs express the phenotype of multidrug resistance, chemotherapy is rarely efficient. [4][5][6] However, RCCs are supposed to be immunogenic; [7][8][9][10][11] hence, immunotherapeutic strategies are dominant. [12][13][14][15] Application of IL-2, [16][17][18][19][20] IFN-a [21][22][23][24] or the combination of IL-2 plus IFN-a [25][26][27][28] also together with fluorouracil and vinblastine 29 have been reported to significantly improve the 3-year survival rate.…”