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Toxicologic Pathology, Vol. 32, No. 1 suppl, 116-121 (2004)
DOI: 10.1080/01926230490426507

Cancer Therapeutics: Understanding the Mechanism of Action

Russell C. Cattley

Department of Pathology, Amgen Inc., rcattley{at}amgen.com

Bert R. Radinsky

Departmen of Cancer Pharmacology, Amgen Inc., Thousand Oaks, California, USA

An intended consequence of the significant investment to characterize the mammalian genome, and its alterations in neoplastic diseases, has been the discovery and commercialization of new approaches to anticancer therapy. As a result, the list of available targets, formerly directed against the processes of DNA replication and mitosis, or in hormonal regulation of growth of tissue, has been dramatically extended. Many of the newer targets represent normal or aberrant signaling pathways, and are present within the cancer cell as second messengers, on its surface (as receptors), or in the external milieu (as ligands). These targets are, therefore, important to the cancer cell phenotype, and affect proliferation, differentiation, and death options for the cell. Another group of targets encompass the cancer cell's relationship to the tissue environment (both stroma and nonneoplastic cells). These targets involve interactions with blood supply (angiogenesis), immune function (evasion), and matrix (invasion and metastasis). Thus, most targets are directly or indirectly critical to some aspect of cancer cell physiology, although a few additional targets are being approached as localization signals for the delivery of otherwise less specific chemotherapeutic or radiotherapeutic agents. The development of new therapeutic approaches has expanded the scope of research required to characterize the mechanism of action for anticancer agents in preclinical models and in clinical trials. In preclinical research, mechanism of action studies have supported the selection of therapeutic agents, appropriate models of efficacy, and experimental design, as well as rational characterization and prediction of nontumor (host) effects. In clinical research, mechanism of action studies have supported the identification of surrogate markers of efficacy (critical for determining adequacy of dose and latency of response), and the selection of patient subpopulations and tumor subtypes most likely to exhibit clinical responses. Finally, information on mechanism of action may suggest strategies for combination therapies and predict potential mechanisms of disease resistance to therapy.

Key Words: Cancer therapy • targeted therapeutics • growth signals • Epidermal Growth Factor Receptor • antibodies • angiogenesis.

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