Abstract
The promising treatment combination of ionizing radiation (IR) with a hypoxia-activated prodrug (HAP) is based on biological cooperation. Here we investigated the hypoxia-activated prodrug evofosfamide in combination with different treatment regimens of IR against lung A549- and head&neck UT-SCC-14-derived tumor xenografts. DNA damage-related endpoints and clonogenic cell survival of A549 and UT-SCC-14 carcinoma cells were probed under normoxia and hypoxia.Evofosfamide (TH-302) induced DNA-damage and a dose-dependent antiproliferative response in A549 cells on cellular pretreatment under hypoxia, and supra-additively reduced clonogenic survival in combination with IR. Concomitant treatment of A549-derived tumor xenografts with evofosfamide and fractionated irradiation induced the strongest treatment response in comparison to the corresponding neoadjuvant and adjuvant regimens. Adjuvant evofosfamide was more potent than concomitant and neoadjuvant evofosfamide when combined with a single high dose of IR. Hypoxic UT-SCC-14 cells and tumor xenografts thereof were resistant to evofosfamide alone and in combination with IR, most probably due to reduced P450 oxidoreductase expression, which might act as major predictive determinant of sensitivity to HAPs.In conclusion, evofosfamide with IR is a potent combined treatment modality against hypoxic tumors. However, the efficacy and the therapeutic outcome of this combined treatment modality is, as indicated here in preclinical tumor models, dependent on scheduling parameters and tumor type, which is most probably related to the status of respective HAP-activating oxidoreductases. Further biomarker development is necessary for the launch of successful clinical trials.
Highlights
Radiotherapy, along with surgery and chemotherapy is one of the major treatment options for solid tumors
The combined treatment modality of ionizing radiation (IR) with an Hypoxia-Activated Prodrug (HAP) is based on biological cooperation
The dosage and schedule of evofosfamide was defined based on previous preclinical reports when used as part of a combined treatment modality [15] and closely mimic the settings used in clinical practice
Summary
Radiotherapy, along with surgery and chemotherapy is one of the major treatment options for solid tumors. Several strategies have been developped during the last decades to overcome the hurdle of tumor hypoxia for successful radiotherapy [1,2,3,4] One of these concepts is based on biological cooperation, which refers to strategies that target distinct cell populations, or employ different mechanisms for cell killing. Despite the clarity of the concept, severe toxicities of these www.impactjournals.com/oncotarget early generation compounds have contributed that these hypoxic radiosensitizers did not find their recognition in the clinical routine. These findings paved the way for the generation of hypoxia-selective bioreductive prodrugs, which are activated by enzymatic reduction in hypoxic tissues [9]
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