Chemosensitization of solid tumors by modulation of resistance mechanisms

The number of drugs available for chemotherapy is growing exponentially, and this trend looks set to continue. Chemosensitization strategies use the administration of one drug or agent to render cancer cells more susceptible to a second agent. Modulation of resistance mechanisms due to xenobiotic membrane pumps such as the multidrug resistant proteins, MDR1/P-glycoprotein or MRP is feasible and a number of new agents have been produced to inhibit drug efflux resulting from expression of these molecules. However, tumor cells may express or upregulate more than one such molecule at one time, and this approach is unlikely to benefit every patient. Detoxification mechanisms mediated by glutathione conjugation or metallothionein are also responsible for resistance--the former has been linked to MRP-mediated resistance. Again, modulation is possible but may increase the toxicity of drugs to normal tissues and an increased therapeutic index is not guaranteed. Tumors exposed to DNA damaging agents often upregulate DNA repair mechanisms and this contributes to resistance. Different pathways perform the repair of different forms of DNA damage, and it is difficult to inhibit all of these. Nevertheless, inhibition of DNA repair can re-sensitize tumors to chemotherapy and is increasingly exploited. One of the most successful and widely used approaches is to combine gemcitabine with an alkylating or platinating agent. While gemcitabine may inhibit DNA polymerases directly, this cytidine analog is also likely to be incorporated by DNA repair leading to activity against non-cycling cells, which form the majority of the neoplastic cell population in most solid tumors. Oncologists should take account of potential resistance mechanisms when treating patients: it is often feasible to design combinations with old or new drugs which exploit these apparent weaknesses to the patient's advantage.