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Evofosfamide sensitizes esophageal carcinomas to radiation without increasing normal tissue toxicity.


ABSTRACT: BACKGROUND AND PURPOSE:Esophageal cancer incidence is increasing and is rarely curable. Hypoxic tumor areas cause resistance to conventional therapies, making them susceptible for treatment with hypoxia-activated prodrugs (HAPs). We investigated in vivo whether the HAP evofosfamide (TH-302) could increase the therapeutic ratio by sensitizing esophageal carcinomas to radiotherapy without increasing normal tissue toxicity. MATERIALS AND METHODS:To assess therapeutic efficacy, growth of xenografted esophageal squamous cell (OE21) or adeno (OE19) carcinomas was monitored after treatment with TH-302 (50?mg/kg, QD5) and irradiation (sham or 10?Gy). Short- and long-term toxicity was assessed in a gut mucosa and lung fibrosis irradiation model, sensitive to acute and late radiation injury respectively. Mice were injected with TH-302 (50?mg/kg, QD5) and the abdominal area (sham, 8 or 10?Gy) or the upper part of the right lung (sham, 20?Gy) was irradiated. Damage to normal tissues was assessed 84 hours later by histology and blood plasma citrulline levels (gut) and for up to 1?year by non-invasive micro CT imaging (lung). RESULTS:The combination treatment of TH-302 with radiotherapy resulted in significant tumor growth delay in OE19 (P?=?0.02) and OE21 (P?=?0.03) carcinomas, compared to radiotherapy only. Irradiation resulted in a dose-dependent decrease of crypt survival (P?

SUBMITTER: Spiegelberg L 

PROVIDER: S-EPMC6913516 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Evofosfamide sensitizes esophageal carcinomas to radiation without increasing normal tissue toxicity.

Spiegelberg Linda L   van Hoof Stefan J SJ   Biemans Rianne R   Lieuwes Natasja G NG   Marcus Damiënne D   Niemans Raymon R   Theys Jan J   Yaromina Ala A   Lambin Philippe P   Verhaegen Frank F   Dubois Ludwig J LJ  

Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 20190817


<h4>Background and purpose</h4>Esophageal cancer incidence is increasing and is rarely curable. Hypoxic tumor areas cause resistance to conventional therapies, making them susceptible for treatment with hypoxia-activated prodrugs (HAPs). We investigated in vivo whether the HAP evofosfamide (TH-302) could increase the therapeutic ratio by sensitizing esophageal carcinomas to radiotherapy without increasing normal tissue toxicity.<h4>Materials and methods</h4>To assess therapeutic efficacy, growth  ...[more]

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