Innovative Chemotherapy: Investigation of the Multidrug Resistant Phenotype

In: Chemotherapy

21 Nov 2014

Innovative Chemotherapy: Investigation of the Multidrug Resistant PhenotypeInvestigation of the Multidrug Resistant Phenotype
Multidrug resistance is a common clinical problem in lung cancer. In SCLC, most tumors recurring after chemotherapy manifest this phenotype, while some demonstrate it prior to therapy. In contrast, most NSCLC and carcinoid tumors demonstrate de novo resistance. While there are many possible reasons for chemoresistance to multiple agents including those that the tumor cells have not been exposed to, one of the best studied mechanisms is over-expression of a 170,000 dalton membrane protein (F-glycoprotein) encoded by the MDRl gene. F-glycoprotein functions as an energy-dependent efflux pump, removing many (but not all) cytotoxic drugs from the cell before they can exert their cytotoxic effects. The MDRl gene is expressed as a 4.5 kb mRNA in some normal tissues, including colonic mucosa, renal proximal tubules, biliary ducts and adrenal cortex and medulla. Click Here

Relatively low expression is present in most other tissues, including lung. In a large survey of human tumors, Goldstein et al“ found that MDR1 RNA levels were usually elevated in untreated, intrinsically drug-resistant tumors arising from colon, adrenal, liver and pancreas, as well as carcinoids. Elevated levels were present only occasionally in most other tumor types. In an effort to determine the role oiMDRl in drug resistance oflung cancer, we measured its expression in a wide spectrum oflung cancer tumors and cell lines. Almost all nontumorous lung tissues, lung cancer tumors and cell lines expressed low levels of RNA. Relatively higher levels were found in 2/5 carcinoids and 4/5 NSCLC lines and tumors expressing multiple neuroendocrine properties. No evidence of gene amplification or rearrangements were detected. We found no correlation between MDR1 expression in cell lines and prior therapy status of the patients, or to the in vitro sensitivity of the cell lines. Thus, the clinical and in vitro multidrug resistance of many lung cancers and their cell lines cannot be explained on die basis of MDR1 expression. Our prediction is that calcium channel blockers are unlikely to have a major impact on the therapy oflung cancer unless they have some biologic effects on tumor cells independent of reversal of F-glycopro-tein. Mechanisms of drug resistance other than MDRl expression may occur, including alterations in the cellular glutathione system, altered function of DNA topoisomerase II and over-expression of metallotheionein genes. We are investigating the role of these factors in lung cancer,u and also the possibility that oncogene amplification or overexpression may confer drug resistance.


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