Novel strategies for overcoming multildrug resistance in cancer

The problems of why metastatic cancers develop pleiotropic resistance to all available therapies, and how this might be countered, are the most pressing in cancer chemotherapy. It is likely that such resistance involves a combination of mechanisms including changes in drug transport/drug targets, reduction in the degree of drug-induced apoptosis/cell loss, and increased rate of tumour repopulation following therapy. Current research must consider not only which mechanisms contribute, eventually relating this to individual patients with cancer, but also what strategies might be utilised to counter each of the important resistance mechanisms. A considerable amount of work has been devoted to the development of inhibitors of membrane-associated transport proteins such as P-glycoprotein, which mediate drug efflux. This work is now being complemented by approaches that target cell death pathways such as those mediated by release of mitochondrial proteins and by activation of surface receptors such as Fas. Rapid progress has been made in developing small-molecular-weight drugs that influence the rate of apoptosis, for instance by binding to the bcl-2 family of proteins regulating mitochondrial permeability. Antisense approaches aimed at reducing bcl-2 expression, and thus increasing the rate of cell death, are also showing promise. Modification of repopulation kinetics provides a further approach but has not received as much attention as other aspects of tumour resistance. New therapeutic approaches will have to be complemented by improved diagnostic tests to evaluate the contributions of different resistance mechanisms in individual patients with cancer.