Cancer Therapies Utilizing the Camptothecins: A Review of the in Vivo Literature

Abstract

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 inactivity at 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 inhibiting 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 non-covalently 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.

Production of valuable compounds by molds and yeasts

“…A review of the activities of camptothecin and its many small and macromolecular derivatives has been published by Venditto and Simanek. 74 Chemically produced derivatives of camptothecin used for cancer include 10-hydroxycamptothecin, topotecan, irinotecan and SN-38. Camptothecin is a multibillion dollar anticancer drug and the fourth largest anticancer drug derived from plants after taxol, vincristine and vinblastine.…”

Glutathione-sensitive nanoplatform for monitored intracellular delivery and controlled release of Camptothecin

“…To address these targets, we have developed a novel camptothecin nanoplatform based in a mercapto-functionalized silica hybrid containing a non-porous core and a mesoporous shell. A new synthetic strategy has been implemented by reacting novel (pyridin-2-yldisulfanyl)alkyl carbonate derivatives of camptothecin (CPT, a topoisomerase I inhibitor) 18,19 with thiol groups of the inorganic support. This allowed us to attach the drug over the pores of the external coating by a cleavable disulfide linker, sensitive to thiols such as glutathione (GSH) or dithiothreitol (DTT), which are able to release the naked molecule after an intramolecular cyclization mechanism.…”

Effects of curcumin on growth of human cervical cancer xenograft in nude mice and underlying mechanism

“…On the one hand, the safe and efficient new anticancer drugs can be screened out from the plants, including paclitaxel (Skwarczynski et al, 2006), camptothecin (Venditto & Simanek, 2010), etc. On the other hand, the new compounds from plants can provide unique chemical structures for design of more ideal drugs.…”