Antiangiogenic metronomic therapy for children with recurrent embryonal brain tumors.

BACKGROUND: Median survival time of recurrent embryonal brain tumors is short regardless of salvage chemotherapy used. An evolving alternative approach to conventional chemotherapy is to target neovascularization by interfering with tumor angiogenesis at various levels. PROCEDURE: From November 2006 to December 2010, 16 patients (median age: 9 years) with recurrent (9 first, 7 multiple) embryonal brain tumors were treated with an antiangiogenic multidrug combination regimen (bevacizumab, thalidomide, celecoxib, fenofibrate, etoposide, and cyclophophamide) and additional intraventricular therapy (etoposide and liposomal cytarabine). RESULTS: At a median of 33 months, 10/16 patients are alive. 4/4 patients with CNS primitive neuroectodermal tumors (CNS PNET) and 1/7 patients with medulloblastoma (MB) died of tumor progression during the first year. Another patient with MB died of an accident after 23 months, the remaining five patients with MB are alive for 12, 33, 33, 37, and 58 months. For the seven patients with MB, both overall survival (OS) and event free survival (EFS) after 6 months was 100%, after 12 months 85.7 ± 13%, and after 24 months 68.6 ± 19%. In contrast, for patients with CNS PNET, both OS and EFS after 6 months was 75.0 ± 22% and 0.0% and all patients had died by 12 months. Low-dose oral etoposide and cyclophosphamide was reduced after a median of 2 months and discontinued after a median of 11 months. Toxicities were manageable and therapy was generally well tolerated. CONCLUSION: Our results suggest that the chosen antiangiogenic drug combination is particularly beneficial for patients with MB and warrants further investigation.

Inhibition of inducible nitric oxide synthesis by Cimicifuga racemosa (Actaea racemosa, black cohosh) extracts in LPS-stimulated RAW 264.7 macrophages.

OBJECTIVES: Cimicifuga racemosa (Actaea racemosa, black cohosh) is used as an anti-inflammatory, antipyretic and analgesic remedy in traditional medicines. The present study focuses on the effects of C. racemosa root extracts on inducible nitric oxide synthase (iNOS) in lipopolysaccharide-stimulated murine macrophages (RAW 264.7). METHODS: C. racemosa rhizome and phosphate-buffered saline extracts were analysed for phenolcarboxylic acids and triterpene glycosides using an HPLC photodiode array/evaporative light-scattering detector system. iNOS was characterised by measurement of iNOS protein (immunoblotting), iNOS mRNA (semiquantitative competitive RT-PCR), nitric oxide production (nitrite levels) and nuclear translocation of nuclear factor-kappaB (p65 subunit) protein. KEY FINDINGS: Incubation of lipopolysaccharide-stimulated macrophages with aqueous C. racemosa extracts (0-6 mg/ml) inhibited nitrite accumulation in a concentration-dependent manner. C. racemosa extracts also reduced iNOS protein expression and iNOS mRNA levels in a dose-dependent manner. C. racemosa extracts did not significantly inhibit iNOS activity and did not affect nuclear translocation of nuclear factor-kappaB (p65 subunit) protein. Incubation with the extract was associated with a concentration-dependent reduction of interferon beta and interferon regulatory factor 1 mRNA. Among the triterpene glycosides, 23-epi-26-deoxyactein was identified as an active principle in C. racemosa extracts. CONCLUSIONS: Extracts from the roots of C. racemosa inhibit nitric oxide production by reducing iNOS expression without affecting activity of the enzyme. This might contribute to the anti-inflammatory activities of C. racemosa.