Journal
JOURNAL OF NEUROSURGERY
Volume 98, Issue 3, Pages 570-577Publisher
AMER ASSOC NEUROLOGICAL SURGEONS
DOI: 10.3171/jns.2003.98.3.0570
Keywords
camptothecin; camptothecin analog; glioma; drug delivery; polymer
Categories
Funding
- NCI NIH HHS [U01-CA52857, CA-09574] Funding Source: Medline
Ask authors/readers for more resources
Object. The authors compared and characterized several new classes of camptothecin (CPT) analogs (a total of 22 drugs) directed against human and murine glioma cell lines in vitro, trying to identify CPT analogs that can be used for local therapy in future clinical trials. Camptothecin is a naturally occurring alkaloid that inhibits the DNA-replicating enzyme topoisomerase I. Moreover, CPT and its analogs have shown promising antitumor activity against both systemic and intracranial neoplasms. Because the CPTs have poor bioavailability and are unable to cross the blood-brain barrier, they may best be delivered to the central nervous system by polymers. The authors have previously shown that local delivery of Na-CPT by implantable polymers prolongs survival in a rat intracranial glioma model. In recent years, a number of newly synthesized CPT analogs have been developed that exhibit more potency and stability than Na-CPT. Methods. Cytotoxicities of the drugs were tested using modified clonogenic and monotetrazolium assays in three glioma cell lines. A potassium chloride-sodium dodecyl sulfate coprecipitation assay was used to determine the frequency of drug-stabilized cleavable complexes. Of the CPT analogs analyzed, the 10, 11-methylenedioxy (MD) class consistently demonstrated the greatest cytotoxicity. Three of these analogs, 10, 11-MD-20(RS)-CPT, 10, 11-MD-20(S)-CPT-glycinate ester (Gly).HCl, and 9-amino-10, 11-MD-20(S)-CPT-Gly, exhibit significantly greater antiproliferative activities than CPT, Na-CPT, or 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) against all three glioma cell lines. In addition, the 10, 11-MD-20(RS)-CPT analog induces more cleavable complexes than Na-CPT at every concentration. Conclusions. The increased potency and greater stability of CPT analogs hold promise for more effective local antitumor treatments against malignant intracranial brain tumors. The greater cytotoxicity of 10, 11-MD CPTs in comparison with other CPT analogs as well as CPT, BCNU, or Na-CPT, may present an ideal candidate drug class for development against both primary and metastatic brain tumors.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available