Drug resistance in ovarian cancer: the emerging importance of gene transcription and spatio-temporal regulation of resistance

Abstract

Resistance to carboplatin plus paclitaxel, one of the most active drug combinations in ovarian cancer, is the major barrier to the successful long-term treatment of this disease. Understanding the mechanisms involved is a first step towards rational strategies to overcome drug resistance and is an area of intense research effort. Recent work has identified several gene families which appear to contribute to the evolution of drug resistance and which are involved in regulating DNA damage, apoptosis and survival signalling. These genes may be co-ordinately regulated as part of a gene expression program that confers drug resistance through multiple pathways. The subcellular localisation of the gene products and their kinetic regulation following exposure to chemotherapeutic agents may also play a part in the development of drug resistance. This provides a more complex paradigm for drug resistance in which the steady-state expression of a single gene may not be predictive of response to therapy. Nevertheless, the identification of critical genes, most relevant to the development of clinical drug resistance, is now feasible through microarray analysis of tumour samples, and strategies aimed at the circumvention of resistance can be developed using these data.