o-(chloroacetylcarbamoyl)fumagillol and Glioma

Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Cyclohexanes; Endothelial Growth Factors; Epidermal Growth Factor; Fibroblast Growth Factor 1; Fibroblast Growth Factor 2; Glioma; Humans; Lymphokines; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Prognosis; Sesquiterpenes; Suramin; Transforming Growth Factor alpha; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Topics: Animals; Antibiotics, Antineoplastic; Cyclohexanes; Endothelial Growth Factors; Glioma; Humans; Lymphokines; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Receptor Protein-Tyrosine Kinases; Receptors, Growth Factor; Receptors, Vascular Endothelial Growth Factor; Sesquiterpenes; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

The effect of the anti-angiogenic agent TNP-470 on tumor growth, vascular area, vascular density and tumor perfusion of two different subcutaneously implanted human glioma xenografts (E98 and E106) in nude mice was evaluated. Vascular parameters were investigated with an image analysis system. For both tumor lines a small but significant tumor growth suppression was observed. However, no differences in vascular parameters between TNP-470 treated tumors and controls could be found after 6 weeks of treatment. It is concluded that although TNP-470 is a promising anti-angiogenic agent in many tumor types, at least 2 glioma lines seem to be partly resistant to its anti-angiogenic effects. Further evaluation of the effects of combination of TNP-470 and cytostatic agents or radiotherapy in human glioma xenografts are required to determine the place of anti-angiogenic therapy in general and treatment with the anti-angiogenic agent TNP-470 more specifically in the treatment of human gliomas.

Topics: Animals; Antibiotics, Antineoplastic; Cell Division; Cyclohexanes; Glioma; Humans; Injections, Subcutaneous; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes; Skin Neoplasms; Transplantation, Heterologous

The angiogenic phenotype is associated with hyperpermeable capillaries. Through treatment with angiogenesis inhibitors capillary permeability may be reduced, and it can be anticipated that cytotoxic agents coadministered may be adversely affected. The current investigation examined this possibility for the combination of TNP-470, an angiogenesis inhibitor, and temozolomide (TMZ), a DNA-alkylating agent with demonstrated activity in brain tumors. TNP-470 (30 mg/kg) was given s.c. on days 6, 8, 10, 12, and 14 following s.c. implantation of rat C6 glioma cells in Sprague-Dawley rats. On the 15th day following tumor implantation, control (no TNP-470) and treated rats received 40 mg/kg of TMZ intraarterially. Prior to dosing, a linear microdialysis probe was placed in the tumor to collect interstitial fluid. Plasma and interstitial fluid samples were collected for 8 h and measured for TMZ by a high-performance liquid chromatography assay. Pharmacokinetic parameters for TMZ were calculated by noncompartmental methods. Total systemic clearance (39.8 +/- 7 versus 44.2 +/- 14 ml min(-1) kg(-1)) and volume of distribution (5.4 +/- 2 versus 5.2 +/- 0.8 L kg(-1)) were not significantly different in control and TNP-470-treated animals. However, the mean TMZ area under the interstitial fluid concentration-time curve was reduced by 25% in the TNP-470-treated group compared to the control (5450 +/- 1892 versus 4120 +/- 1790 micrograms min ml(-1); P < 0.05). It appears that TNP-470 caused this reduction in the tumor uptake of TMZ by its pharmacodynamic action on the tumor vasculature. Since combination regimens using angiogenesis inhibitors and cytotoxic drugs will be needed to determine how such combinations can be used effectively. The current animal model, which utilized tumor microdialysis, can serve as a model to further analyze combination chemotherapy.

Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents, Alkylating; Brain Neoplasms; Cyclohexanes; Dacarbazine; Factor VIII; Glioma; Microscopy, Confocal; Neoplasm Transplantation; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Rats; Sesquiterpenes; Temozolomide; Tumor Cells, Cultured

A novel angiogenesis inhibitor TNP-470 was investigated for its anti-tumor activity against malignant gliomas both in vitro and in vivo. TNP-470 cytostatically inhibited the growth in all of the seven glioma cell lines in culture including anticancer drug resistant cells. The 50% inhibitory concentrations (IC50) of these glioma cell lines were 10 to 30 micrograms/ml and they were 10 to 20 times higher than IC50 of normal endothelial cells. TNP-470 (30 mg/kg, i.p., every other day) also significantly inhibited the tumor growth of T98G-transplanted nude mice. Microscopically, tumor vessels after the treatment of the tumor-bearing mice with TNP-470 became fewer in number and smaller in diameter than those without treatment. Furthermore, there appeared extensive necrotic areas in the tumor with TNP-470. These results indicate that TNP-470 is a potent angiogenesis inhibitor for malignant gliomas. In addition, the studies of labeling index of BrdU and Ki67 suggest that TNP-470 may act mainly on tumor endothelial cells, thus resulting in reduction of the tumor growth.

Topics: Animals; Antibiotics, Antineoplastic; Brain Neoplasms; Cyclohexanes; Drug Resistance; Drug Screening Assays, Antitumor; Glioma; Humans; Mice; Mice, Nude; O-(Chloroacetylcarbamoyl)fumagillol; Rats; Sesquiterpenes; Tumor Cells, Cultured