Protective effect on normal brain tissue during a combinational therapy of 2-deoxy-d-glucose and hypofractionated irradiation in malignant gliomas

Abstract

Purpose:To investigate the effect of 2-deoxy–D-glucose (2-DG), an inhibitor of glucose transport and glycolysis, on glioblastoma and the normal brain tissue during combined treatment with hypofractionated radiotherapy.Materials and Methods:Twenty patients with malignant gliomas (18 Glioblastoma Multiformae, 2 Anasplastic Astrocytoma grade III) following surgery were treated weekly (once) with 2-DG, (250 mg/kg body weight), followed by 5 Gy of radiation to the tumor bed per fraction for 7 weeks. Clinical evaluation, complete hemogram, and random blood sugar levels were carried out in each cycle. Follow-up computed tomography (CT)/magnetic resonance imaging (MRI) was done to evaluate radiation-induced changes. Kernofsky Performance scale (KPS) was recorded preoperatively; postoperatively, and post-therapy till the last follow-up.Results:Twenty patients were recruited for this trail; 19 of them completed the treatment and 1 discontinued. The survival period ranged between 6 and 36 months after the treatment, with a median survival of 14 months. CT and MRI revealed significant tumor necrosis. Histological evidence from the tissue during reexploration confirms the hypothesis of protective effect of 2-DG on normal brain. KPS was above 80% in majority of the patients, 6 months after the surgery.Conclusion:Radiotherapy coupled with 2-DG enhances tumor necrosis selectively and significantly while the normal brain gets relatively protected. This has been reflected in our study both clinically by preservation of quality-of-life and pathologically by retaining the integrity of normal brain architecture.

<p>T-Regulatory Cells In Tumor Progression And Therapy</p>

“…133,134 Moreover, in phase-I-III clinical trials, negligible normal tissue toxicity, enhanced survival and significant improvement in the quality of life has been observed in cerebral glioma patients following administration of 2-DG with hypofractionated radiotherapy. 40,[133][134][135][136][137] Results from murine studies have shown that the response of the tumors to the combined treatment of 2-DG and irradiation is heterogeneous with complete (cure; tumor-free survival) and partial (growth delay) response, which correlates well with the immune stimulation, switch of Th2 cells to Th1 cells and a significant reduction in Treg numbers in spleen, peripheral blood, lymph node and tumor. 133,134,138 However, significant effects on Treg cells was not observed in the non-tumor bearing mice, suggesting a differential effect of 2-DG on Tregs in normal and tumor-bearing mice.…”

Targeting glucose metabolism in cancer: a new class of agents for loco-regional and systemic therapy of liver cancer and beyond?

“…At higher doses, dose-limiting side effects occurred in two of six patients [37]. Adapting the recommended treatment schedule in another clinical trial, surgical re-exploration and histological tumor analysis in 13 of 20 patients revealed extensive tumor necrosis with surrounding tissue being well-preserved [38]. …”

Cell cycle synchronisation using thiazolidinediones affects cellular glucose metabolism and enhances the therapeutic effect of 2-deoxyglucose in colon cancer

“…As far as we know, this study is the first investigation about the therapeutic effects of combination therapy using cell cycle synchronisation and 2-DG in mouse tumour models. Until now, several preclinical and clinical studies have been performed to evaluate the efficacy of 2-DG treatment in combination with chemotherapy or radiation therapy in lung cancer, osteosarcoma, and human cerebral glioma [11][12][13][14] . Although, results from those studies lacked consensus, 2-DG showed significant improvement in achieving partial or complete response when used prior to radiotherapy or following chemotherapeutic drugs, such as adriamycin, paclitaxel or etoposide.…”