Oncotarget

Research Papers:

The hypoxia-activated prodrug evofosfamide in combination with multiple regimens of radiotherapy

Katarzyna J. Nytko, Ivo Grgic, Sabine Bender, Janosch Ott, Matthias Guckenberger, Oliver Riesterer and Martin Pruschy _

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Oncotarget. 2017; 8:23702-23712. https://doi.org/10.18632/oncotarget.15784

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Abstract

Katarzyna J. Nytko1,2, Ivo Grgic1,2, Sabine Bender1, Janosch Ott1, Matthias Guckenberger3, Oliver Riesterer2,3, Martin Pruschy1,2

1Laboratory for Applied Radiobiology, Department of Radiation Oncology, University Hospital Zurich, Zurich, Switzerland

2Clinical Research Priority Program “Tumor Oxygenation”, Zurich, Switzerland

3Department of Radiation Oncology, University Hospital Zurich, Zurich, Switzerland

Correspondence to:

Martin Pruschy, email: martin.pruschy@usz.ch

Keywords: evofosfamide, TH-302, hypoxia-activated prodrug, ionizing radiation, P450 oxidoreductase

Received: June 29, 2016     Accepted: February 06, 2017     Published: February 28, 2017

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.


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