Metronomic Oral Topotecan with Pazopanib Is an Active Antiangiogenic Regimen in Mouse Models of Aggressive Pediatric Solid Tumor

Abstract

Purpose Low dose metronomic (LDM) chemotherapy, combined with VEGF signaling pathway inhibitors, is a highly effective strategy to coordinately inhibit angiogenesis and tumor growth in many adult preclinical cancer models. We have tested the efficacies of daily oral LDM topotecan alone and in combination with pazopanib, a VEGF receptor inhibitor, in three pediatric extracranial solid tumor mouse models. Experimental Design In vitro dose–response study of topotecan and pazopanib was conducted on several neuroblastoma, osteosarcoma, and rhabdomyosarcoma cell lines. In vivo antitumor efficacies of the LDM topotecan and pazopanib as single agents and in combination were tested on 4 subcutaneous xenograft models and on 2 neuroblastoma metastatic models. Circulating angiogenic factors such as circulating endothelial cells (CEC), circulating endothelial progenitor cells (CEP), and microvessel densities were used as surrogate biomarker markers of antiangiogenic activity. Results In vitro, topotecan caused a dose-dependent decrease in viabilities of all cell lines, while pazopanib did not. In vivo, combination of topotecan + pazopanib (TP + PZ) showed significant antitumor activity and significant enhancement in survival compared with the respective single agents in all models. Reductions in viable CEP and/or CEC levels and tumor microvessel density were correlated with tumor response and therefore confirmed the antiangiogenic activity of the regimens. Pharmacokinetic studies of both drugs did not reveal any drug–drug interaction. Conclusion Metronomic administration of TP + PZ showed a statistically significant antitumor activity compared with respective single agents in pediatric tumor mouse models and represent a valid option as a maintenance therapy in aggressive pediatric solid tumors.

Combined Antitumor Therapy with Metronomic Topotecan and Hypoxia-Activated Prodrug, Evofosfamide, in Neuroblastoma and Rhabdomyosarcoma Preclinical Models

“…In our previous studies, we showed that maximal plasma concentration (C max ) of topotecan was 19.8 ng/mL with the metronomic oral dose of 1 mg/kg drug administration in NOD/SCID mouse model (23). In patients, C max of topotecan Tables 1 and 2, with the presence of topotecan, evofosfamide-induced cytotoxicity was significantly enhanced under overnight hypoxia as indicated by decreased IC 50 s in most tested tumor cell lines.…”

“…It has been shown active in diverse tumor types, including metastatic disease, especially when combined with antiangiogenic drugs (27)(28)(29)(30). The availability of the oral topotecan, along with our previous studies combining metronomic topotecan with pazopanib in neuroblastoma preclinical models (23), suggest that oral metronomic topotecan may be an ideal candidate for pediatric solid tumors. Considering the limited effects on hypoxic tumors with conventional chemotherapy, hypoxia-targeting cytotoxic agents along with topotecan therapy may achieve greater antitumor activities.…”

“…The combination of topotecan, cyclophosphamide, and etoposide is tolerable and effective in relapsed and newly diagnosed neuroblastoma in phase II clinical trials and upfront phase III clinical trials (18,21). Single-agent topotecan has also been found to be antiangiogenic in preclinical models of pediatric cancers (22,23). Despite initial response, tumors eventually acquire resistance to topotecan.…”

Metronomic chemotherapy regimens in oncology

“…Аналогично: добавление TNP-470 (антиангиогенного агента) к низким дозам доксифлуридина значимо тор-мозит рост карциносаркомы на животных моделях по сравнению с монотерапией данными агентами [63]. Комбинация пазопаниба и низких доз топотекана так-же приводит к противоопухолевому эффекту и выра-женному уменьшению плотности микрососудистого русла при раке яичников [64][65][66].…”

“…Темозоломид -алкилирующий препарат II поко-ления, относящийся к классу имидазотетразинов, обладающий высокой биодоступностью и способно-стью проникать через гематоэнцефалический барьер [64,[70][71][72][73]. В метрономных режимах применяется обычно в дозе 75 мг / м 2 , хотя дозировки варьируют по данным различных исследований [65,74].…”