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Monday 01 January 2007

Interferon beta-mediated vessel stabilization improves delivery and efficacy of systemically administered topotecan in a murine neuroblastoma model.

By: Dickson PV, Hagedorn NL, Hamner JB, Fraga CH, Ng CY, Stewart CF, Davidoff AM.

J Pediatr Surg 2007 Jan;42(1):160-5; discussion 165.

BACKGROUND: We have recently demonstrated that continuous delivery of interferon beta (IFN-beta) stabilizes solid tumor vasculature and improves tumor perfusion. In this study, we have further investigated the functional consequences of this effect by assessing delivery and efficacy of conventional chemotherapy against neuroblastoma xenografts when used in combination with IFN-beta. METHODS: Mice with established retroperitoneal tumors received adeno-associated virus vector encoding IFN-beta (AAV IFN-beta) or control vector. One week later, at 1 hour before sacrifice, a 1 mg/kg i.v. bolus of topotecan (TPT) was given. Intratumoral levels of TPT were measured by high-performance liquid chromatography and then standardized to plasma levels to determine tumor TPT penetration. Subsequent experiments evaluated the antitumor efficacy of topotecan alone or in combination with AAV IFN-beta. RESULTS: As observed in prior experiments, AAV IFN-beta resulted in a marked increase in tumor vessel association with stabilizing perivascular smooth muscle cells. These more "matured" vessels facilitated improved tumor TPT penetration (51.2% +/- 4.2%) compared with controls (30.8% +/- 4.7%, P = .004). In additional cohorts of mice, this resulted in an improved antitumor effect. Mice with established tumors (301.8 +/- 18.1 mm3) were treated with TPT (1 mg/kg daily for 5 days for 2 consecutive weeks) either alone or in combination with AAV IFN-beta (5 x 10(10) vector particles per mouse). Topotecan monotherapy resulted in a reduction in mean tumor volume of 12% (264.2 +/- 65.8 mm3, P = .66). However, when the same regimen was administered to mice receiving continuous IFN-beta therapy, a 61% (118.9 +/- 42.3 mm3, P = .004) reduction in mean tumor volume was achieved. CONCLUSION: Interferon beta-mediated vessel stabilization resulted in improved intratumoral delivery of systemically administered TPT, enhancing its antitumor efficacy. This approach of altering the tumor vasculature provides a strategy to help overcome solid tumor resistance to traditional cytotoxic agents.

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