Abstract
Re-irradiation is challenging for esophageal cancer patients with local-regional recurrence after initial radiotherapy. The purpose of this study is to establish a recurrent esophageal tumor model and investigate radiosensitizing effects of sodium glycididazole (CMNa). Tumor models were established by pre-irradiation (0 Gy, 10 Gy or 20 Gy) to the right hind leg of the nude mice 24 hours before tumor transplantation (ECA109 human esophageal carcinoma cells). Tumor growth curves were analyzed. Hypoxic microenvironment was exhibited in tumor frozen slides stained for pimonidazole, Hoechst 33342, hematoxylin-eosin and CD34. Mice bearing primary (0 Gy pre-irradiation) and recurrent (10 Gy pre-irradiation) tumors were randomized into control (no treatment), radiation (30 Gy in 3 weekly fractionations), or radiation combined with CMNa (1 mmol/kg i.p. injected 60 min before radiation) respectively. The data showed tumors from 10 Gy and 20 Gy pre-irradiated sites grew significantly slower than those in the 0 Gy pre-irradiated group. The recurrent xenograft tumors showed increased necrotic fractions, decreased micro-vascular density, increased pimonidazole-positive fraction, and decreased Hoechst-positive fraction. In the primary xenograft tumors, CMNa adding to radiation did not lead to significant tumor growth delay than radiation alone. However, for the recurrent tumor model, the growth rate was remarkably reduced as CMNa combined with radiation as comparison with radiation alone. In conclusion, the recurrent esophageal xenograft model with tumor bed effect was successfully established characterized by slow growth, increased hypoxia fraction and decreased blood flow. Significant radiosensitization by CMNa was demonstrated in the recurrent model.
Highlights
Radiotherapy is the mainstay in management of esophageal carcinoma [1, 2]
Recurrent tumors were often found to be resistant to re-irradiation, resulted in poor disease control and limited survival [6, 9, 10]. This could be due to the condition known as “tumor bed effect” (TBE), which showed tumors in pre-irradiated beds commonly characterized by reduced blood perfusion, extensive necrosis, and elevated hypoxic fractions
The hypoxic microenvironment and radiosensitizing role of CMNa in pre-clinical models of recurrent primary tumors were studied in the present work by using ECA109 human esophageal xenografts growing in un-irradiated and pre-irradiated beds in BALB/c-nu/nu mice
Summary
Radiotherapy is the mainstay in management of esophageal carcinoma [1, 2]. local-regional recurrence after radiotherapy was about 40~50% despite of advancing radiation techniques and advanced chemotherapy/targeted therapy [3, 4]. The radiobiological characteristics of recurrent tumor after radiotherapy are different from the primary tumors [5, 6]. Tumor transplanted into pre-irradiated tissue has been frequently used as www.impactjournals.com/oncotarget recurrent xenograft tumor models [5,6,7,8]. Recurrent tumors were often found to be resistant to re-irradiation, resulted in poor disease control and limited survival [6, 9, 10]. This could be due to the condition known as “tumor bed effect” (TBE), which showed tumors in pre-irradiated beds commonly characterized by reduced blood perfusion, extensive necrosis, and elevated hypoxic fractions. Recurrent tumor model in esophageal cancer was not well-documented
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