1. Evofosfamide sensitizes esophageal carcinomas to radiation without increasing normal tissue toxicity
- Author
-
Ludwig Dubois, Stefan J. van Hoof, Raymon Niemans, Frank Verhaegen, Jan Theys, R. Biemans, Ala Yaromina, Linda Spiegelberg, Natasja G. Lieuwes, Damiënne Marcus, Philippe Lambin, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Promovendi ODB, Radiotherapie, Precision Medicine, Ondersteunend personeel ODB, and RS: GROW - R2 - Basic and Translational Cancer Biology
- Subjects
Male ,0301 basic medicine ,Radiation-Sensitizing Agents ,Esophageal Neoplasms ,medicine.medical_treatment ,Esophageal cancer ,Short-term gut toxicity ,Gastroenterology ,TUMOR HYPOXIA ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,TOTAL-BODY IRRADIATION ,HYPOXIA-ACTIVATED PRODRUG ,TH-302 ,Therapeutic index ,Long-term lung fibrosis ,Hematology ,CANCER ,3. Good health ,medicine.anatomical_structure ,PHASE-I ,Oncology ,Nitroimidazoles ,030220 oncology & carcinogenesis ,Toxicity ,Female ,Phosphoramide Mustards ,medicine.medical_specialty ,DOXORUBICIN ,Adenocarcinoma ,Article ,Late Radiation Injury ,03 medical and health sciences ,Cell Line, Tumor ,Internal medicine ,medicine ,INJURY ,Animals ,Humans ,Radiology, Nuclear Medicine and imaging ,COMBINATION ,Lung ,Evofosfamide ,PRO-DRUG TH-302 ,Radiotherapy ,Squamous Cell Carcinoma of Head and Neck ,business.industry ,Histology ,medicine.disease ,Radiation therapy ,030104 developmental biology ,chemistry ,business - Abstract
Highlights • TH-302 combined with RT enhances tumor growth delay in esophageal cancer models. • This combination does not increase normal tissue toxicity on the short and long term. • The increased therapeutic index (1.38) paves the way for future clinical trials., 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
- Published
- 2019