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 language | English (US) |
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Pages (from-to) | 361-367 |
Number of pages | 7 |
Journal | Cancer Chemotherapy and Pharmacology |
Volume | 54 |
Issue number | 4 |
DOIs | |
State | Published - 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)