Metronomic treatment of temozolomide inhibits tumor cell growth through reduction of angiogenesis and augmentation of apoptosis in orthotopic models of gliomas

Abstract

Abstract. Glioblastoma is a highly angiogenic tumor with a dismal prognosis. Temozolomide (TMZ), a methylating agent is one of the most effective chemotherapeutic agents against glioblastoma. To overcome the problem that most of these tumors become resistant to chemotherapeutic regimens within a year, we investigated the antitumor efficacy of metronomic administration of low-dose TMZ in in vitro cell proliferation/ cytotoxicity assay and in vivo rat and nude mouse orthotopic glioma model. By in vitro assay, we elucidated that C6/LacZ rat glioma cells were more resistant to metronomic treatment of TMZ than U-87MG human glioblastoma cells and bEnd.3 mouse brain endothelial cells. Compared with the conventional chemotherapeutic regimen of TMZ, we found that frequent administration of TMZ at a low dose (metronomic treatment) markedly inhibited angiogenesis as well as tumor growth in a TMZ-resistant C6/LacZ rat glioma model. In addition, metronomic treatment of TMZ significantly augmented apoptosis of tumor cells in this model. For the TMZ-sensitive U-87MG cells, even with a very low dose of TMZ, which is not effective to reduce tumor mass, the metronomic treatment of TMZ reduced the microvessel density, i.e. angiogenesis, in a nude mouse orthotopic model. In conclusion, for both models, the metronomic treatment of TMZ decreased angiogenesis. Especially, in TMZ-resistant glioma cells, this regimen increased apoptosis of tumor cells and decreased tumor growth. The metronomic treatment of TMZ in orthotopic glioma models demonstrated a successful antiangiogenic effect which can overcome the chemoresistance in conventional TMZ chemotherapy. IntroductionMalignant gliomas are the most common subtypes of rapidly growing primary brain tumors in adults and the most angiogenic human tumors which are characterized by a remarkable proliferative vascular component (1). They have retained their poor prognosis despite aggressive diverse conventional therapeutic approaches, requiring us to find novel therapeutic strategies (2). Particularly, for management of the growth of tumors including gliomas, which are dependent on angiogenesis, i.e. proliferation of microvascular endothelial cells, vascular targeted therapy has been the focus of recent studies.Temozolomide (TMZ) exhibits broad-spectrum antitumor activity on diverse tumors such as human melanoma, ovarian, colon and brain tumors (3-5). It is a DNA alkylating agent and an imidazotetrazine derivative used in the therapy of malignant gliomas (6,7). Since it has lipophilic property, TMZ is orally available and has shown excellent tissue distribution, including penetration across the blood-brain barrier (3). Although TMZ possesses good antitumor activity, its application in the management of high-grade glioma is limited by various resistant mechanisms (8), which leads many studies to explore the optimization of antitumor efficacy through combination of TMZ with radiation therapy or another agent (6,9-11). It was also reported that the antitumor activity of TMZ is found to be highly ...

Combined therapy of temozolomide and ZD6474 (vandetanib) effectively reduces glioblastoma tumor volume through anti-angiogenic and anti-proliferative mechanisms

“…It was developed as a DNA alkylating agent that directly damages tumor cells (5)(6)(7). TMZ is stable in acidic conditions, but breaks down to 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC) and forms methyldiazonium ions in alkaline conditions, such as the blood.…”

“…Temozolomide (TMZ) is the most widely used chemotherapy for GBM and is orally administered (5). TMZ is a small-molecule DNA alkylating agent that easily penetrates the blood-brain barrier and elicits DNA methylation to effect tumor cell death (6,7).…”

Antiangiogenic Strategies for Treatment of Malignant Gliomas

“…95 In glioma animal models, metronomic chemotherapy is an effective antiangiogenic strategy. 96 Earlier studies evaluating metronomic chemotherapy in recurrent MG patients reported favorable toxicity profiles, but no significant survival benefits were observed. [97][98][99] Recently, two reports evaluating low-dosed, frequently administered temozolomide schedules in recurrent GBM patients documented modest gains in PFS6 proportions, relative to historical controls.…”

Synergistic inhibition of angiogenesis and glioma cell-induced angiogenesis by the combination of temozolomide and enediyne antibiotic lidamycin

“…27 As to TMZ, its applications in clinic and preclinical have obtained encouraging results with anti-angiogenic and anti-tumor effects in glioma therapy, 36,37 and the reported experimental and clinic practices has confirmed the potential role of TMZ combined with other agents in glioma growth delay. Combinations of the two drugs exerted enhanced apoptosis ratios to rBMeC cells (D).…”