Antineoplastic drug resistance in brain tumors

Abstract

For all neoplasms, extraneural as well as brain, intrinsic, and acquired resistance to antineoplastic drugs constitutes a multifactorial problem. Much information has been generated concerning the individual mechanisms that play a role in drug resistance. The present decade will see a great deal of laboratory research emphasis in two related areas: (1) the molecular biology of resistance, including processes that regulate gene expression for critical detoxifying and transport proteins, and (2) further identification of DNA repair mechanisms in normal and neoplastic cells. In addition to continued research directed toward the identification of specific mechanisms, further study of the interrelationship between these mechanisms will be essential. Finally, there is a growing awareness that in vitro determination of the rank order of mechanisms contributing to resistance for a given drug may be quite different from that determined in vivo. The complexity of this problem is increased for brain tumors in that the understanding of the fundamentals of brain tumor biology is less advanced than for many of the systemic tumors. Ultimately, the identification of resistance mechanisms will lead to the development of clinically useful approaches to reverse cellular resistance and to increase drug sensitivity. Examples of such strategies that have or will find their way into clinical trial include: (1) use of buthionine sulfoximine to reverse glutathione-mediated resistance, (2) use of ethacrynic acid to reverse glutathione S-transferase-mediated resistance, and (3) use of calcium channel blockers and calmodulin inhibitors to reverse MDR. There will also be considerable emphasis on the rational modification of existing antineoplastic agents and the development of new drugs designed to circumvent important resistance mechanisms. For brain tumor treatment, additional strategies to circumvent intrinsic and acquired resistance by increasing drug delivery, such as high-dose chemotherapy with marrow or growth factor rescue and local drug delivery to brain tumors by drug-impregnated biodegradable polymers, will continue to be examined. Previous experience with efforts to augment antineoplastic drug cytotoxicity indicates that this process may decrease the margin of cytotoxicity between normal tissue and tumor, often referred to as the therapeutic index. To avoid serious neurotoxicity as a dose-limiting or treatment-limiting factor for potentially important clinical strategies to modulate drug resistance, it will be important to develop a greater understanding of the relative treatment sensitivities of brain capillary endothelium, glial cells, and neurons, as well as their individual abilities to transport, detoxify, and repair the effects of these drugs.(ABSTRACT TRUNCATED AT 400 WORDS)