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Camptothecins in Cancer Therapy pp 171–190Cite as

Recent Advances in Camptothecin Drug Design and Delivery Strategies

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

Abstract

Camptothecin (CPT) (Fig. 1) and its related analogs are an expanding class of anticancer agents that have the potential to effect a broad and significant clinical impact (1–15). Clinical interest in the CPTs is in large part based on their unique mode of action: these agents turn topoisomerase I (TOP-I), an enzyme that alleviates the torsional stress of supercoiled DNA, into an intracellular poison. The CPTs stabilize the covalent binding of TOP-I to its DNA substrate and the formation of these complexes leads to reversible, single-strand nicks. Initially, the nicks do not negatively affect the cellular viability; however, according to the fork collision model, the nicks are ultimately converted to irreversible and lethal double-strand breaks during DNA synthesis. As a result of this mechanism of action, the CPTs are regarded as being S-phase specific agents and are therefore toxic to cells that are actively replicating DNA (11,16,17). Because of their proliferating nature, cancerous cells spend more time in the S-phase relative to normal cells. Also, it has been shown that TOP-I is overexpressed in a variety of tumor lines (8,15). Logically, the accelerated rate of cell replication and the overexpression of TOP-I provide a limited basis for selectivity through which the CPTs can generate greater cytotoxicity against cancerous cells than against normal cells.

Camptothecin hydrolysis at physiological pH.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY

    Thomas G. Burke PhD, Tian-Xiang Xiang PhD & Bradley D. Anderson PhD

  2. Experimental Therapeutics Program, Lucille P. Markey Cancer Center, University of Kentucky Medical Center, University of Kentucky, Lexington, KY

    Thomas G. Burke PhD & Tian-Xiang Xiang PhD

  3. Tigen Pharmaceuticals Inc., Lexington, KY

    Thomas G. Burke PhD & Lori J. Latus MD

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Editors and Affiliations

  1. Department of Pharmacy Practice and Science, College of Pharmacy, University of Kentucky, Lexington, KY

    Val R. Adams PharmD

  2. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY

    Thomas G. Burke PhD

  3. Experimental Therapeutics Program, Lucille P. Markey Cancer Center, University of Kentucky Medical Center, University of Kentucky, Lexington, KY

    Thomas G. Burke PhD

  4. Tigen Pharmaceuticals Inc., Lexington, KY

    Thomas G. Burke PhD

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Burke, T.G., Xiang, TX., Anderson, B.D., Latus, L.J. (2005). Recent Advances in Camptothecin Drug Design and Delivery Strategies. In: Adams, V.R., Burke, T.G. (eds) Camptothecins in Cancer Therapy. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1385/1-59259-866-8:171

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