Anticancer drug resistance in primary human brain tumors

The difficult clinical situation still associated with most types of primar y human brain tumors has fostered significant interest in defining novel th erapeutic modalities for this heterogeneous group of neoplasms. Beginning i n the 1980s chemotherapy has been incorporated into the treatment protocol of a number of intractable brain tumors. However, it has predominantly fail ed to improve patient outcome. The unsatisfactory results with chemotherape utic intervention have chiefly been attributed to tumor cell resistance. In recent years, there has been a literal explosion in our understanding abou t the mechanisms by which cancer cells become chemoresistant. During the co urse of their evolution (intrinsic resistance) or in response to chemothera py (acquired resistance) these cells may follow a number of pathways of gen etic alterations to possess a common (multidrug) or drug-specific (individu al 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 th e genesis of chemotherapeutic treatment failure. Although, through the year s we have come to yield information and inferences as to the roles that dif ferent molecular events may have in the resistance phenotype of cancer cell s, 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 circ le, hinder the development of effective resistance-modulation strategies. C linical non-responsiveness to chemotherapy remains a formidable obstacle to the successful treatment of brain tumors and one of the most serious probl ems to be solved in the therapy of these lesions. Future advances in the ch emotherapeutic management of these neoplasms will come with an improved und erstanding of the significance and interrelationship of the multiple biolog ical 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 Scienc e B.V. All rights reserved.