The difficult clinical situation still associated with most types of primary human brain tumors has fostered significant interest in defining novel therapeutic modalities for this heterogeneous group of neoplasms. Beginning in the 1980s chemotherapy has been incorporated into the treatment protocol of a number of intractable brain tumors. However, it has predominantly failed to improve patient outcome. The unsatisfactory results with chemotherapeutic intervention have chiefly been attributed to tumor cell resistance. In recent years, there has been a literal explosion in our understanding about the mechanisms by which cancer cells become chemoresistant. During the course of their evolution (intrinsic resistance) or in response to chemotherapy (acquired resistance) these cells may follow a number of pathways of genetic alterations to possess a common (multidrug) or drug-specific (individual drug) resistant phenotype. Genomic aberrations, deregulation of membrane transporting proteins and cellular enzymes, and an altered susceptibility to commit to apoptosis are among the steps on the way that contribute to the genesis of chemotherapeutic treatment failure. Although, through the years we have come to yield information and inferences as to the roles that different molecular events may have in the resistance phenotype of cancer cells, the actual involvement of single genetic alterations in conferring drug resistance in primary brain tumors remains debatable. This uncertainty and, besides, the lack of proper drug resistance diagnostics, in a vicious circle, hinder the development of effective resistance-modulation strategies. Clinical non-responsiveness to chemotherapy remains a formidable obstacle to the successful treatment of brain tumors and one of the most serious problems to be solved in the therapy of these lesions. Future advances in the chemotherapeutic management of these neoplasms will come with an improved understanding of the significance and interrelationship of the multiple biological systems operative in promoting resistance to this treatment modality. The focus of this review is to summarize current knowledge concerning major drug resistance-related markers, to describe their functional interaction en route to chemoresistance, and to discuss their implication in rendering human brain tumor cells resistant to chemotherapy. (C) 2001 Elsevier Science B.V. All rights reserved.
