Journal Article Radiotherapy Synergizes with the Hypoxia-Activated Prodrug Evofosfamide: In Vitro and In Vivo Studies.

Takakusagi, Yoichi  ,  Kishimoto, Shun  ,  Sarwat, Naz  ,  Matsumoto, Shingo  ,  Saito, Keita  ,  Hart, Charles  ,  B Mitchell, James  ,  C Krishna, Murali

2017-11 , Mary Ann Libert
AIMS:Evofosfamide (TH-302) is a hypoxia-activated prodrug (HAP) that releases the DNA-damaging bromo-isophosphoramide mustard (Br-IPM) moiety selectively under hypoxic conditions. Since solid tumors are known to have hypoxic regions, HAPs in combination with chemotherapy or radiotherapy (XRT) will be beneficial. We tested the oxygen dependence of release kinetics of Br-IPM using electron paramagnetic resonance (EPR) with spin trapping by monitoring redox cycling of the nitroimidazole moiety of TH-302, and oxygen dependence of TH-302 on in vitro cytotoxicity at different levels of hypoxia was also examined. Two tumor implants (SCCVII and HT29) in mice were studied.RESULTS:TH-302 fragmentation to release Br-IPM was noticed at oxygen levels <76 mmHg, which increased with higher levels of hypoxia. Enhanced cellular cytotoxicity was also observed at oxygen levels <76 mmHg. In vivo pO2 imaging in the two tumor implants showed that the SCCVII tumor implant had higher level of hypoxia compared with the HT29 xenograft. TH-302 as a monotherapy in vivo showed modest effects in SCCVII implants and minimal effects in HT29 xenografts, whereas TH-302 in combination with ionizing radiation showed significant benefit in both tumor models.INNOVATION:We examined the kinetics of redox cycling versus fragmentation of TH-302. The combination of oxygen-dependent XRT with TH-302 is effective even in tumors with significant hypoxia.CONCLUSIONS:Imaging studies identifying the magnitude of hypoxia in tumors indicated that the responsiveness to TH-302 and the antitumor effect of TH-302 were enhanced by combining with XRT in both the TH-302-sensitive SCCVII tumor and -resistant HT29 tumor.

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