P-glycoprotein: clinical significance and methods of analysis

Multidrug resistance (MDR) is responsible for a decrease in sensitivity of tumor cells tumor cells to unrelated, naturally occurring anticancer drugs. This resistance is correlated with expression and activity of a membrane protein, P-gp 170, functioning as a drug-extruding pump. It has been well described in in vitro situations; however, the clinical detection and implications are not yet clear. Multiple detection assays have been developed based on the discovery of the MDR gene family and the corresponding protein. Southern, Northern, or Western blot analysis, S1 nuclease protection or PCR-based assays, immunohistochemical detection or functionality tests by flow cytometry have been used extensively. However, by use of these techniques on clinical material, both normal and malignant, contradictory results have emerged. The sensitivity and specificity of a certain technique are always limited by unavoidable parameters, for example, skill of the technician. Moreover, the complexity of the development of resistance against anticancer agents (external determinants), such as the diversity of tumor tissues, the simultaneous presence of other resistance mechanisms, and the low expression level, make MDR detection equivocal and can lead to contradictory results. Previous treatment influencing the MDR profile and inappropriate timing of the test make a possible correlation between MDR expression and chemotherapeutic resistance difficult to establish and can lead to discordant results. In this review, the need for proper criteria is stressed. No single detection technique provides the ideal test to detect MDR. Tandem testing could give more certainty, although small sample size limit this application. Formulation of a standard assay with better definition of a positivity is essential before clinical trials are started.