Advances in rational combination chemotherapy

Due to the high frequency of micro- or macrometastatic disease at the time of diagnosis of cancer, and to the increasing prevalence of cancer in this country, the use of chemotherapy to evoke cure or prolongation of survival has become critically important. In addition, the growth kinetics of large tumor burdens and the high probability of drug-resistant cells in a tumor mass at the time of diagnosis necessitate combinations of chemotherapeutic agents rather than single agents as the most effective mode of treatment. Since there are 40 to 50 active anticancer drugs now utilized, and since synergy between drug combinations is often dose and/or schedule dependent, the number of possible drug combinations and permutations is vast. Thus, screening for effective drug combinations requires a rational approach which will allow for accurate predictions of synergy. Most advances in this scientific approach have utilized biochemical modulation in conjunction with in vitro cytotoxicity assays, in particular, clonogenic assays. Such an approach has generated a number of drug combinations, such as sequential MTX-5FU, with widely applicable clinical efficacy. The continued use of biochemical modulation should rapidly generate new effective drug combinations which will, hopefully, allow us to cure even those cancers presently considered incurable.