belotecan and Glioblastoma

The prognosis of patients diagnosed with glioblastoma remains dismal in spite of the current concomitant chemoradiotherapy with temozolomide. In particular, the resistance to temozolomide appears to be the greatest obstacle to the treatment of glioblastoma. In the present study, we evaluated in vitro and in vivo the antitumor effects of combination therapy of cilengitide with belotecan, a camptothecin derivate, to treat experimental glioblastoma. The therapeutic effects of the drugs on the U87MG and U251MG human glioblastoma cell lines were assessed using in vitro cell viability and apoptosis assays. The combination treatment group with cilengitide and belotecan enhanced the cytotoxic effects to the glioblastoma cell lines and increased the apoptosis of the tumor cells compared to monotherapy with either drug alone in vitro. Nude mice with established U87MG glioblastoma were assigned to the following four groups: control, cilengitide, belotecan and combination treatment. The volume of tumors and length of survival were also measured. Animals in the combination therapy group demonstrated a significant reduction of tumor volume and an increase in survival (p < 0.05). Immunohistochemistry revealed a decrease in angiogenesis by cilengitide and an increase in apoptosis by cilengitide and belotecan in vivo. The combination therapy of cilengitide with belotecan presented more cytotoxic effects compared to the monotherapy of either drug in vitro and in vivo. This combination protocol may serve as an alternative treatment option for glioblastoma.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Brain Neoplasms; Camptothecin; Cell Line, Tumor; Cell Proliferation; Cell Survival; Glioblastoma; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Neovascularization, Pathologic; Snake Venoms; Topoisomerase I Inhibitors; Xenograft Model Antitumor Assays

CKD-602 7-[2-(N-isopropylamino)ethyl]-(20S)-camptothecin, belotecan) is a synthetic water-soluble camptothecin derivative and topoisomerase inhibitor that has been shown to have clinical anticancer effect against ovarian and lung cancer. We studied its anticancer effects on four human glioma cell lines, U87 MG, U343 MG, U251 MG and LN229. Cell viability was quantified by a modified 2-(2-methoxy-4-nitropheyl)-3-(4-nitropheyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt and significant time- and dose-dependent cytotoxicity was observed in all cell lines. Susceptibility to CKD-602 at 48 h after treatment varied among the four cell lines and their IC50 value was as follows: 9.07 nM (95% CI 0.18-37.42) for LN229, 14.57 nM (95% CI 0.86-47.33) for U251 MG, 29.13 nM (95% CI 0.35-101.23) for U343 MG, and 84.66 nM (95% CI 34.63-148.25) for U87 MG. CKD-602 induced cell cycle arrest at G2 phase and produced antiproliferative activity and apoptosis in all cell lines. Thus, CKD-602 showed a significant anticancer effect on glioma cells in vitro and is a promising candidate for further studies on malignant gliomas.

Topics: Antineoplastic Agents; Apoptosis; Brain Neoplasms; Camptothecin; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Enzyme Inhibitors; Glioblastoma; Humans; Inhibitory Concentration 50; Time Factors; Topoisomerase I Inhibitors