Basis for effective combination cancer chemotherapy with antimetabolites

Most current chemotherapy regimens for cancer consist of empirically design ed combinations, based on efficacy and lack of overlapping toxicity. In the development of combinations, several aspects are often overlooked: (1) pos sible metabolic and biological interactions between drugs, (2) scheduling, and (3) different pharmacokinetic profiles. Antimetabolites are used widely in chemotherapy combinations for treatment of various leukemias and solid tumors. Ideally, the combination of two or more agents should be more effec tive than each agent separately (synergism), although additive and even ant agonistic combinations may result in a higher therapeutic efficacy in the c linic. The median-drug effect analysis method is one of the most widely use d methods for in vitro evaluation of combinations. Several examples of clas sical effective antimetabolite-(anti)metabolite combinations are discussed, such as that of methotrexate with 6-mercaptopurine or leucovorin in (child hood) leukemia and 5-fluorouracil (5FU) with leucovorin in colon cancer. Mo re recent combinations include treatment of acute-myeloid leukemia with flu darabine and arabinosylcytosine. Other combinations, currently frequently u sed in the treatment of solid malignancies, include an antimetabolite with a DNA-damaging agent, such as gemcitabine with cisplatin and 5FU with the c isplatin analog oxaliplatin. The combination of 5FU and the topoisomerase i nhibitor irinotecan is based on decreased repair of irinotecan-induced DNA damage. These combinations may increase induction of apoptosis. The latter combinations have dramatically changed the treatment of incurable cancers, such as lung and colon cancer, and have demonstrated that rationally design ed drug combinations offer new possibilities to treat solid malignancies. ( C) 2000 Elsevier Science Inc. All rights reserved.