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Hypoxia-Targeting Drug Evofosfamide (TH-302) Enhances Sunitinib Activity in Neuroblastoma Xenograft Models
- Source :
- Translational Oncology, Vol 11, Iss 4, Pp 911-919 (2018), Translational Oncology
- Publication Year :
- 2018
- Publisher :
- Elsevier, 2018.
-
Abstract
- Antiangiogenic therapy has shown promising results in preclinical and clinical trials. However, tumor cells acquire resistance to this therapy by gaining ability to survive and proliferate under hypoxia induced by antiangiogenic therapy. Combining antiangiogenic therapy with hypoxia-activated prodrugs can overcome this limitation. Here, we have tested the combination of antiangiogenic drug sunitinib in combination with hypoxia-activated prodrug evofosfamide in neuroblastoma. In vitro, neuroblastoma cell line SK-N-BE(2) was 40-folds sensitive to evofosfamide under hypoxia compared to normoxia. In IV metastatic model, evofosfamide significantly increased mice survival compared to the vehicle (P=.02). In SK-N-BE(2) subcutaneous xenograft model, we tested two different treatment regimens using 30 mg/kg sunitinib and 50 mg/kg evofosfamide. Here, sunitinib therapy when started along with evofosfamide treatment showed higher efficacy compared to single agents in subcutaneous SK-N-BE(2) xenograft model, whereas sunitinib when started 7 days after evofosfamide treatment did not have any advantage compared to treatment with either single agent. Immunofluorescence of tumor sections revealed higher number of apoptotic cells and hypoxic areas compared to either single agent when both treatments were started together. Treatment with 80 mg/kg sunitinib with 50 mg/kg evofosfamide was significantly superior to single agents in both xenograft and metastatic models. This study confirms the preclinical efficacy of sunitinib and evofosfamide in murine models of aggressive neuroblastoma. Sunitinib enhances the efficacy of evofosfamide by increasing hypoxic areas, and evofosfamide targets hypoxic tumor cells. Consequently, each drug enhances the activity of the other.
- Subjects :
- 0301 basic medicine
Drug
Original article
Cancer Research
media_common.quotation_subject
lcsh:RC254-282
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Neuroblastoma
medicine
media_common
Evofosfamide
business.industry
Sunitinib
Hypoxia (medical)
Prodrug
medicine.disease
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
In vitro
030104 developmental biology
Oncology
chemistry
Apoptosis
030220 oncology & carcinogenesis
Cancer research
medicine.symptom
business
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 19365233
- Volume :
- 11
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Translational Oncology
- Accession number :
- edsair.doi.dedup.....d1e066225ea8e9f89e91bca2c2ce4db7