Cancer therapies utilizing the camptothecins: a review of the in vivo literature.
This review summarizes the in vivo assessment-preliminary, preclinical, and clinical-of chemotherapeutics derived from camptothecin or a derivative. Camptothecin is a naturally occurring, pentacyclic quinoline alkaloid that possesses high cytotoxic activity in a variety of cell lines. Major limitations of the drug, including poor solubility and hydrolysis under physiological conditions, prevent full clinical utilization. Camptothecin remains at equilibrium in an active lactone form and inactive hydrolyzed carboxylate form. The active lactone binds to DNA topoisomerase I cleavage complex, believed to be the single site of activity. Binding inhibits DNA religation, resulting in apoptosis. A series of small molecule camptothecin derivatives have been developed that increase solubility, lactone stability and bioavailability to varying levels of success. A number of macromolecular agents have also been described wherein camptothecin(s) are covalently appended or noncovalently associated with the goal of improving solubility and lactone stability, while taking advantage of the tumor physiology to deliver larger doses of drug to the tumor with lower systemic toxicity. With the increasing interest in drug delivery and polymer therapeutics, additional constructs are anticipated. The goal of this review is to summarize the relevant literature for others interested in the field of camptothecin-based therapeutics, specifically in the context of biodistribution, dosing regimens, and pharmacokinetics with the desire of providing a useful source of comparative data. To this end, only constructs where in vivo data is available are reported. The review includes published reports in English through mid-2009.
Venditto
Vincent J
VJ
Department of Chemistry, Texas A&M University, College Station, Texas 77843, USA.
Simanek
Eric E
EE
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*
D000970:Antineoplastic Agents; D002166:Camptothecin