Intracellular Signaling Targets for Cancer Chemosensitization

Thomas G. Gesnerand Stephen D. Harrison Chiron Corporation, Emeryville, CA 94608

Introduction - Chemotherapy and radiation exposure are the major options for the treatment of cancer. The application of both of these therapies is limited by severe adverse effects on normal tissues and the frequent development of tumor cell resistance. It is therefore highly desirable to improve the efficacy of these treatments without increasing the toxic side effects and to counteract the resistance mechanisms that can render tumors insensitive to therapy.

In this review we will focus on the sensitization of tumors to chemotherapy. Most chemotherapeutic agents are cytotoxic drugs that kill cancer cells by interfering with the cell cycle and inducing cell death, either by disrupting nucleotide precursor synthesis, inducing DNA damage or impairing the function of microtubules. Intrinsic and acquired resistance to such chemotherapy may result from a number of mechanisms that fall into broad classes. These are: decreased accumulation of the drug (e.g. by efflux pump overexpression); limitation of drug-induced injury (e.g. by glutathione overproduction); mutations in the target protein (e.g. topoisomerase I); repair of DNA damage or alterations in the cellular signaling pathways that regulate the cell cycle and cell death. Targeting of the former mechanisms has been extensively discussed (1,2). However as our understanding of the cell cycle has improved we have been able to identify a number of cell signaling proteins that may be effectively targeted to sensitize tumor cells to cytotoxic drugs. It is these latter targets that form the basis for this review.

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