Current Cancer Drug Targets - Volume 1, Issue 1, 2001

The time course and duration of action of drugs used in cancer chemotherapy are greatly influenced by the molecular and biochemical properties of enzymes associated with their metabolism. Variation in the response of individual patients to cancer chemotherapeutic agents is in large measure due to genetic and environmental factors that impinge on specific enzymes belonging to the two major classes of drug metabolizing enzymes. Current knowledge of the molecular biology and biochemistry of phase I drug metabolizing enzymes (cytochrome P450, flavin-containing and xanthine oxidases, NADPH quinone reductase, and aldehyde and dihydropyridine dehydrogenases), and phase II enzymes (glucuronosyl-, sulfo-, N-acetyl-, and glutathione transferases, and hydrolases) is reviewed briefly. Advances in understanding genetic and environmental factors that influence activities of phase I and phase II pathways of drug metabolism are discussed in the first sections of this review followed by a consideration of the influence of drug metabolism on the actions of agents currently used in the treatment of cancer. Emphasis is given to drugs that have recently been introduced into the armamentarium of cancer chemotherapy including inhibitors of chromatin function, target-based inhibitors of signal transduction and cyclin-dependent kinases, and angiogenesis inhibitors acting on metalloproteinases, epithelial cell growth, angiogenesis stimulation, and endothelial-specific integrins.

Cancer drug therapy is undergoing a major transition from the previous pregenomic cytotoxic era to the new postgenomic era. Future mechanism-based therapeutic agents will increasingly be designed to act on molecular targets that are causally involved in the malignant progression of human cancers. Such agents are predicted to show greater therapeutic selectivity for cancer versus normal cells. New cancer drug targets are identified and validated in various ways. The determination of the normal human genome sequence, followed by that of multiple cancer genomes, is accelerating target discovery. Other new technologies, particularly high throughput screening, combinatorial chemistry and gene expression microarrays, are increasing the speed and efficiency of drug development. Examples of new molecular therapeutics showing promising activity in the clinic include Herceptin, Glivec and Iressa. However, many challenges remain as we test the vision of individualised combinatorial genome-based therapy, using drugs targeted to every significant molecular abnormality in cancer.

The tyrosine kinase inhibitor STI571 exemplifies the successful development of a rationally designed, molecularly targeted therapy for the treatment of cancer. This review details the steps in the development of this agent and highlights why this drug has been so successful in the treatment of chronic myelogenous leukaemia. Future directions including the mechanisms and management of resistance and new therapeutic strategies are discussed. Finally, the literature supporting the use of STI571 in other malignancies, including solid tumors is briefly reviewed.

Recently identified agents that interact with cytoskeletal elements such as tubulin include synthetic spiroketal pyrans (SPIKET) and monotetrahydrofuran compounds (COBRA compounds). SPIKET compounds target the spongistatin binding site of b-tubulin and COBRA compounds target a unique binding cavity on a-tubulin. At nanomolar concentrations, the SPIKET compound SPIKET-P causes tubulin depolymerization and exhibits potent cytotoxic activity against cancer cells. COBRA-1 inhibits GTP-induced tubulin polymerization. Treatment of human breast cancer and brain tumor cells with COBRA-1 caused destruction of microtubule organization and apoptosis. Other studies have identified some promising protein tyrosine kinase inhibitors as anti-cancer agents. These include EGFR inhibitors such as the quinazoline derivative WHI-P97 and the leflunomide metabolite analog LFM-A12. Both LFM-A12 and WHI-P97 inhibit the in vitro invasiveness of EGFR positive human breast cancer cells at micromolar concentrations and induce apoptotic cell death. Dimethoxyquinazoline compounds WHI-P131 and WHI-P154 inhibit tyrosine kinase JAK3 in leukemia cells. Of particular interest is WHI-P131, which inhibits JAK3 but not JAK1, JAK2, SYK, BTK, LYN, or IRK at concentrations as high as 350 μM. Studies of BTK inhibitors showed that the leflunomide metabolite analog LFM-A13 inhibited BTK in leukemia and lymphoma cells. Consistent with the anti-apoptotic function of BTK, treatment of leukemic cells with LFM-A13 enhanced their sensitivity to chemotherapy-induced apoptosis.

Gene expression microarrays and gene expression databases provide new opportunities for the discovery of drug targets and for determination of a drug's mode of action. We review gene expression analysis methods and describe studies that have identified cell cycle genes using differential expression analysis and co-expression analysis. We present an example of the identification of previously-unrecognized human cell cycle genes, CDCA1 through CDCA8, that are co-expressed with known cell cycle genes including CDC2, CDC7, CDC23, cyclin, MCAK, mki67a, topoisomerase II, and others.