The topoisomerase I inhibitor gimatecan exhibits anti-tumor activity against malignant glioma xenografts as single agent and in combination

Abstract

2081 Background: Gimatecan, a novel oral lipohilic camptotecan (ST1481; NVP-LBQ707), has shown to irinotecan and topotecan superior anti-tumor activity against several cell lines and human xenografts. We evaluated gimatecan in microemulsion in vivo alone and in combination with temozolomide and the EGFR and VEGF tyrosine kinase inhibitor AEE788 against subcutaneous malignant glioma xenografts derived from primary tumors. Results: Gimatecan exhibited dose-dependent activity against all three advanced tumor stage glioma models with IGRG93 being the most sensitive: 0.10 to 0.25 mg/kg gimatecan daily orally in a protracted schedule 5 days/week during 4 weeks resulted in 100% partial and complete tumor regressions, significant tumor growth delays (TGD; 48 to >100 days), log cell kills of 4.3 to 9.1, and were thus considered as ++++ highly active according to the SRI activity criteria. Anti-tumor activity in the TP53 wild-type IGRG93 correlated with significant induction of apoptotic cell death, as measured by TUNEL and cell cycle analysis, and lack of induction of p21. Moreover, combination of gimatecan and temozolomide resulted in synergistic activity against the TP53 wild-type IGRG121 glioblastoma and gimatecan at the MTD could be combined with temozolomide without enhanced toxicity. Gimatecan 0.19 mg/kg q5/wx4w combined with AEE788 50 mg/kg q3/wx4w was evaluated against the TP53 mutant, EGFR gene amplified IGRG88 glioma. Both agents were highly active resulting in 100% tumor regression. Gimatecan treated tumors started to grow 2–3 weeks after treatment end, while tumors treated with AEE788 regrew directly after treatment stop resulting in less significant TGD. Gimatecan and AEE788 given simultaneously during 4 weeks yielded less significant TGD compared to gimatecan alone, thus antagonistic effects. AEE788 induced G1 cell growth arrest which may reduce sensitivity to gimatecan, necessitating S-phase to be most efficient. An alternative schedule with gimatecan followed by AEE788 may be more appropriate. Conclusions: Gimatecan is highly active against malignant glioma xenografts and has synergistic activity with temozolomide suggesting this new topoisomerase I inhibitor for the treatment of malignant glioma. No significant financial relationships to disclose.