Camptothecin analogs in malignant gliomas: Comparative analysis and characterization

Prakash Sampath, Eric Amundson, Monroe E. Wall, Betty Mae Tyler, Mansukh C. Wani, Lloyd M. Alderson, Michael Colvin, Henry Brem, Jon David Weingart

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)570-577
Number of pages8
JournalJournal of Neurosurgery
Volume98
Issue number3
StatePublished - Mar 1 2003
Externally publishedYes

Fingerprint

Camptothecin
Glioma
Carmustine
Brain Neoplasms
irinotecan
Cell Line
Pharmaceutical Preparations
Polymers
Type I DNA Topoisomerase
Potassium Chloride
Blood-Brain Barrier
Alkaloids
Sodium Dodecyl Sulfate

Keywords

  • Camptothecin
  • Camptothecin analog
  • Drug delivery
  • Glioma
  • Polymer

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)

Cite this

Sampath, P., Amundson, E., Wall, M. E., Tyler, B. M., Wani, M. C., Alderson, L. M., ... Weingart, J. D. (2003). Camptothecin analogs in malignant gliomas: Comparative analysis and characterization. Journal of Neurosurgery, 98(3), 570-577.

Camptothecin analogs in malignant gliomas : Comparative analysis and characterization. / Sampath, Prakash; Amundson, Eric; Wall, Monroe E.; Tyler, Betty Mae; Wani, Mansukh C.; Alderson, Lloyd M.; Colvin, Michael; Brem, Henry; Weingart, Jon David.

In: Journal of Neurosurgery, Vol. 98, No. 3, 01.03.2003, p. 570-577.

Research output: Contribution to journalArticle

Sampath, P, Amundson, E, Wall, ME, Tyler, BM, Wani, MC, Alderson, LM, Colvin, M, Brem, H & Weingart, JD 2003, 'Camptothecin analogs in malignant gliomas: Comparative analysis and characterization', Journal of Neurosurgery, vol. 98, no. 3, pp. 570-577.
Sampath P, Amundson E, Wall ME, Tyler BM, Wani MC, Alderson LM et al. Camptothecin analogs in malignant gliomas: Comparative analysis and characterization. Journal of Neurosurgery. 2003 Mar 1;98(3):570-577.
Sampath, Prakash ; Amundson, Eric ; Wall, Monroe E. ; Tyler, Betty Mae ; Wani, Mansukh C. ; Alderson, Lloyd M. ; Colvin, Michael ; Brem, Henry ; Weingart, Jon David. / Camptothecin analogs in malignant gliomas : Comparative analysis and characterization. In: Journal of Neurosurgery. 2003 ; Vol. 98, No. 3. pp. 570-577.
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T2 - Comparative analysis and characterization

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AU - Amundson, Eric

AU - Wall, Monroe E.

AU - Tyler, Betty Mae

AU - Wani, Mansukh C.

AU - Alderson, Lloyd M.

AU - Colvin, Michael

AU - Brem, Henry

AU - Weingart, Jon David

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N2 - 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.

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