The molecular genetics of therapeutic resistance in malignant astrocytomas.

Abstract

The adverse prognosis associated with malignant astrocytomas (MA) is due in part to the development of resistance by the tumor to chemo- and radiotherapy-induced cytotoxic damage. The mechanisms of resistance are poorly understood but function at the level of the endothelial cell, the blood-brain barrier and the neoplastic cell itself. The classic examples of drug resistance proteins, such as the p-glycoprotein/multidrug resistance protein 1, have been identified within MA biopsy specimens. However, it is questionable to what degree, if at all, these proteins contribute directly to the evolution and prognosis of the MA. Surprisingly, there are specific genes, not traditionally associated with resistance, which appear increasingly relevant to both tumor progression and insensitivity to cytotoxic damage. These genes are involved in cell cycle regulation, and include the retinoblastoma susceptibility gene (Rb), the tumor suppressor gene p53, as well as those encoding the cyclins, their kinases and inhibitors. The interaction between the products of these genes and intratumoral environmental factors appears to involve a dynamic and prognostically adverse selection process. It is from this perspective that the mechanism(s) of hypoxic-ischaemic selection for resistance and its therapeutic repercussions will be analyzed.