RESUMO
Background: Tumor hypoxia has been frequently detected in nasopharyngeal carcinoma (NPC) and is intently associated with therapeutic resistance. The aim of the study is to establish a clonogenically stable hypoxia-inducible dual reporter model and apply it to investigate the effect of tumor hypoxia on DNA double strand break (DSB) and synergistic effect of irradiation in combination with chemotherapy or targeted therapy. Methods: The plasmid vector consisting of hypoxia response elements to regulate HSV1-TK and GFP genes, was constructed and stably transfected into human NPC cells. The expected clone was identified and validated by in vivo and in vitro assay. DSB repair was measured by γH2AX foci formation. Tumor growth delay assay and spatial biodistribution of various biomarkers was designed to investigate the anti-tumor effect. Results: The system has the propensity of high expression of reporter genes under hypoxia and low to no expression under normoxia. Intratumoral biodistributions of GFP and classic hypoxic biomarkers were identical in poor-perfused region. Upon equilibration with 10% O2, the xenografts showed higher expression of hypoxic biomarkers. Cisplatin radiosensitized SUNE-1/HRE cells under hypoxia by suppressing DSB repair while the addition of PI3K/mTOR inhibitor further enhanced the anti-tumoral therapeutic efficacy. Combination of IR, DDP and NVP-BEZ235 exhibited most effective anti-tumor response in vivo. These observations underline the importance of dual reporter model for imaging tumor hypoxia in therapeutic study. Conclusions: Our preclinical model enables the investigation of heterogeneous tumor hypoxic regions in xenograft tissues and explores the treatment efficacy of combinations of various therapeutic approaches to overcome hypoxia.
RESUMO
To explore clinical characteristics which could be applied to predict pathologic complete response (pCR) for patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy (neo-CRT) and total mesorectal excision (TME). 297 patients with locally advanced rectal cancer (cT3-4 or cN+) who were treated with neo-CRT followed by TME were retrospectively reviewed. Clinical characteristics including age, gender, tumor distance from anus, serum CEA, hemoglobin levels before treatment and clinical TN stage were used to investigate the association with pCR after neo-CRT. Seventy-nine (26.6%) patients achieved pCR after neo-CRT. pCR were achieved in 42 (34.4%) patients in cT1-3 stage and 37 (21.1%) in cT4 stage. pCR rate was 36.4% and 16.4% for patients with pre-treatment serum CEA ≤5.33ng/ml and >5.33ng/ml, respectively. Uni- and multi-variate analyses revealed that pre-treatment serum CEA level ≤5.33ng/ml and clinical T stage, (i.e., cT1-3 versus cT4) were highly correlated with pCR (p < 0.05). Clinical T stage and pre-treatment serum CEA level were strongly associated with pCR for patients with locally advanced rectal cancer treated with neo-CRT followed by TME which could be applied as clinical predictors for pCR.
