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Development of Protein Kinase C and Cyclin-Dependent Kinase Inhibitors As Potentiators of Cytotoxic Drug Action in Leukemia

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Combination Cancer Therapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

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Abstract

During the last decade, the approach to cancer chemotherapy has been revolutionized by two major advances: an accelerated understanding of the cell-death process (apoptosis) (1) and progress in the development of molecularly targeted agents directed against specific oncogenes and enzymes responsible for neoplastic transformation, e.g., STI571 in the case of Bcr/Abl+ malignancies (2). Such efforts have served to focus attention on two general classes of agents: inhibitors of (a) cell-cycle regulation and (b) cytoprotective signal transduction pathways. The rationale for developing cell-cycle inhibitors is based on abundant evidence that neoplastic cells are defective in cell-cycle regulation, i.e., loss of the G1 checkpoint (3). In addition, it is now recognized that a variety of neoplastic cells, particularly those of hematopoietic origin, exhibit increased activity of certain pro-survival signaling pathways, i.e., the Ras/Raf/MEK/MAP kinase cascade (4). Thus, interference with specific cell-cycle progression and/or signaling pathways represents a logical alternative (or adjunct) to the use of cytotoxic agents, which kill neoplastic cells through more general mechanisms.

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  1. Department of Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA

    Steven Grant MD

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  1. Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY

    Gary K. Schwartz MD

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Grant, S. (2005). Development of Protein Kinase C and Cyclin-Dependent Kinase Inhibitors As Potentiators of Cytotoxic Drug Action in Leukemia. In: Schwartz, G.K. (eds) Combination Cancer Therapy. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1385/1-59259-864-1:061

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