Treatment of Poorly Differentiated Glioma Using a Combination of Monoclonal Antibodies to Extracellular Connexin-43 Fragment, Temozolomide, and Radiotherapy

Abstract

Antitumor efficiencies of monoclonal antibodies to connexin-43 second extracellular loop (MAbE2Cx43), temozolomide, and fractionated γ-irradiation in the monotherapy mode and in several optimized combinations were studied in Wistar rats with induced C6 glioma. The survival of animals with glioma and the dynamics of intracerebral tumor development were evaluated by MRT. Temozolomide monotherapy (200 mg/m(2)) and isolated radiotherapy in a total dose of 36 Gy shifted the survival median from 28 days (no therapy) to 34 and 38 days, respectively; 100% animals died under conditions of temozolomide monotherapy and radiotherapy. Monotherapy with MAbE2Cx43 in a dose of 5 mg/kg led to significant regression of the tumor (according to MRT data), cure of 19.23% animals with glioma, and prolongation of the survival median to 39.5 days after tumor implantation. Combined therapy with MAbE2Cx43 and temozolomide completely abolished the antitumor effect (survival median 29 days). Treatment with MAbE2Cx43 in combination with radiotherapy was associated with mutual boosting of the therapeutic efficiencies, leading to a significant inhibition of tumor development and prolongation of the survival median to 60 days. The mechanism of tumorsuppressive activity of the antibodies could be due to connexon blockade in Cx43-positive glioma cells in the peritumor invasion zone. Higher efficiency of combined therapy was presumably due to the increase in blood-brain barrier permeability for antibodies after irradiation of the brain and to additional inhibitory effect of antibodies towards radioresistant migrating glioma cells. The results suggested that MAbE2Cx43 could be effective as the first-line drug in combined therapy for poorly differentiated gliomas.

Gap junctions and cancer: communicating for 50 years

“…In addition to pharmacological approaches to regulate GJIC, Cx43 blocking antibodies have also been shown to reduce tumour growth either alone 232 or in combination with standard cancer therapy 233 . In other novel cases, Cx43 antibodies have been used as a guidance system to deliver diagnostic markers or therapeutic compounds such as cisplatin to Cx43-positive tumour cells 234,235 .…”

Connexin 43 Inhibition Sensitizes Chemoresistant Glioblastoma Cells to Temozolomide

“…Second, overexpressing Cx43 in GBM cell lines rendered them resistant to TMZ (7, 8). Third, genetic knockdown of Cx43 or an antibody against Cx43 restored TMZ sensitivity (6–8). Finally, GBM cells expressing a CT truncation of Cx43 recovered sensitivity to TMZ (8).…”

Blood—brain barrier permeability in healthy rats and rats with experimental C6 glioma after fractionated radiotherapy of the brain

“…Чем выше ее вели-чина, тем быстрее тормозится опухолевый рост, но возрастает число побочных эффектов и риск бы-строй смерти животного. При величине фракции в 4 Гр глиома практически не увеличивалась в объеме, однако по завершению облучения опухолевый рост возобновлялся с удвоенной скоростью [27,31].…”

“…С увеличе-нием разовой дозы одной фракции возрастает сте-пень выраженности когнитивных расстройств [22,29,30], поэтому в исследованиях по проницаемости ГЭБ у предварительно здоровых крыс (без глиомы) были выбраны режимы фракционирования, пока-завшие свою эффективность в быстрой стабилиза-ции объема глиомы С6, но без остро выраженных побочных эффектов, а именно: 4 Гр×6 фракций и длительное облучение небольшими дозами 2 Гр×9 фракций [31].…”