Gene therapy of the typical multidrug resistance phenotype of cancers: a new hope?

The multidrug resistance (MDR) phenotype of cancers has generated a large amount of research, owing to its constant fatal clinical outcome. Many studies have focused on the discovery of chemomodulators; however, in spite of this huge effort, the side effects that these products induce, and their additive toxicity when used in the presence of anticancer drugs, have led to the disaffection of the pharmaceutical industry and possibly slowed down research in pharmacological modulation. New tools developed using molecular biology techniques have opened the way for gene therapy and given birth to new therapeutic hopes. However, these discoveries and especially their clinical applications have slowed due to a lack of knowledge of the systems that finely regulate the MDR genes. This weakness explains why, to date, no general review has focused on the possibilities of gene therapy of MDR derived form the strategic options now available. Based on molecular foundations and recent fundamental discoveries, we seek to inform clinicians of the therapeutic hopes for chemoresistant tumors brought about by potent and specific new tools such as transcriptional decoys, interfering RNAs, etc. After describing the causes and mechanisms of MDR, we critically review these new strategies and their corresponding clinical trials.