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2018 ; 11
(4
): 911-919
Nephropedia Template TP
gab.com Text
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English Wikipedia
Hypoxia-Targeting Drug Evofosfamide (TH-302) Enhances Sunitinib Activity in
Neuroblastoma Xenograft Models
#MMPMID29803017
Kumar S
; Sun JD
; Zhang L
; Mokhtari RB
; Wu B
; Meng F
; Liu Q
; Bhupathi D
; Wang Y
; Yeger H
; Hart C
; Baruchel S
Transl Oncol
2018[Aug]; 11
(4
): 911-919
PMID29803017
show ga
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.