Systemic BCNU enhances the efficacy of local delivery of a topoisomerase I inhibitor against malignant glioma

Phillip B. Storm, Violette M. Renard, John L. Moriarity, Betty Tyler, Robb E. Wilentz, Henry Brem, Jon D. Weingart

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: To investigate the ability of systemically delivered BCNU to enhance the activity of either systemically delivered irinotecan (CPT-11) or locally delivered camptothecin from a biodegradable polymer for treatment of an intracranial 9L gliosarcoma. Methods: We used a single systemic dose of BCNU on treatment day 1 in combination with systemic doses of CPT-11 on treatment days 1-5 and 8-12 against an intracranial rat 9L gliosarcoma model implanted into female Fischer 344 rats. We also used the same systemic dose of BCNU given on treatment day 1, followed by a local dose of a 20% loaded camptothecin biodegradable polymer implanted on the same day. Results: Two doses of CPT-11 (10 and 60 mg/kg) were delivered systemically against intracranial 9L. Neither dose showed an increase in survival compared to controls (P > 0.2 for 10 mg/kg and P = 0.17 for 60 mg/kg). Systemic delivery of CPT-11 (10 mg/kg per day) in combination with systemic BCNU (15 mg/kg) did not show a significant effect on survival compared to systemic BCNU alone (P > 0.2), even at the maximally tolerated systemic dose of CPT-11 (60 mg/kg per day; P = 0.06). The combination of systemic BCNU (15 mg/kg) and intracranial delivery of camptothecin (20% loaded polymer), however, significantly extended survival compared to systemic BCNU alone (P < 0.001) and compared to intracranial delivery of camptothecin alone (P = 0.01). Conclusions: In a 9L gliosarcoma model, systemic delivery of CPT-11 showed no benefit in survival when delivered alone or in combination with systemic BCNU, because CPT-11 is unable to cross the blood-brain barrier in cytotoxic levels. When cytotoxic levels of a topoisomerase I inhibitor are delivered directly to the brain tumor via a biodegradable polymer, however, the systemic delivery of the alkylating agent BCNU significantly enhances the antitumor effects of camptothecin in a 9L gliosarcoma model.

Original languageEnglish (US)
Pages (from-to)361-367
Number of pages7
JournalCancer Chemotherapy and Pharmacology
Volume54
Issue number4
DOIs
StatePublished - Oct 2004

Keywords

  • BCNU
  • Brain tumor
  • CPT-11 (Irinotecan)
  • Camptothecin
  • Combination
  • Polymer delivery
  • Topoisomerase I inhibitor

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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