o-(chloroacetylcarbamoyl)fumagillol and Kidney-Neoplasms

Renal cell carcinoma is resistant to most chemotherapy, and only a minority of patients respond to immunotherapy. Its highly vascular nature suggests that antiangiogenesis therapy might be useful. We thus performed a phase II study of the fumigillin analog TNP-470 in previously treated patients with metastatic renal cell carcinoma.. Metastatic renal cell carcinoma patients with good organ function were entered onto the study through five separate institutions. There were no exclusion criteria for prior therapy. All patients were treated at a dose of 60 mg/m(2) of TNP-470 infused over 1 hour three times per week.. Thirty-three patients were enrolled. Therapy was generally well tolerated, but asthenia, fatigue, vertigo, dizziness, sense of imbalance, and loss of concentration were common and severe enough to lead to therapy discontinuation in five patients. There was only one partial response of short duration (response rate, 3%, 95% confidence interval, 0% to 16%), but six patients (18%) remained on study for 6 or more months without toxicity or disease progression.. Long-term therapy with TNP-470 has manageable toxicities and is feasible in patients with metastatic renal cell carcinoma but does not lead to any significant objective responses. Further studies in this population using TNP-470 schedules that produce more prolonged drug levels and clinical trial end points other than objective tumor regression may be indicated.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Combined Modality Therapy; Cyclohexanes; Disease-Free Survival; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes

The contribution of angiogenesis inhibitor TNP-470 to the growth and metastasis of ACHN renal cell carcinoma (RCC) was studied. TNP-470 (40 mg/kg, every two days) was administrated to BABL/c nude mice bearing ACHN RCC. The mice were sacrificed after a treatment duration of 31 days and the weight and volume of subcutaneous tumors as well as foci of lung metastasis were measured. The microvascular density (MVD) of the tumor as well as the PCNA index and apoptotic index of the tumor cells were evaluated immunohistochemically. Result showed that the growth of ACHN RCC was suppressed significantly and none metastasis was observed in TNP-470-treated mice. Compared with the control group, the MVD was decreased markedly (P < 0.01) and the apoptotic index was increased significantly (P < 0.01) in the treated group. The tumor volume was positively correlated to the MVD (r = 0.7144, P < 0.01) and inversely correlated to the apoptotic index (r = -0.8607, P < 0.01), and MVD was conversely correlated to the apoptotic index. It was determined that TNP-470 could effectively inhibit angiogenesis of ACHN RCC, which resulting in ischemia and hypoxia, leading to increased apoptosis, thus obviously suppressing the growth and metastasis of ACHN RCC in nude mice.

Topics: Angiogenesis Inhibitors; Animals; Apoptosis; Carcinoma, Renal Cell; Cell Division; Cyclohexanes; Female; Kidney Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Random Allocation; Sesquiterpenes

Antiangiogenic therapy is a promising new strategy to inhibit tumor growth and formation of metastases. Vascular endothelial growth factor (VEGF) and its receptors, VEGF-receptor 1 (VEGF-R1; FLT-1) and VEGF-R2 (KDR), have been shown to play a major role in tumor angiogenesis. PTK787/ZK 222584, a specific inhibitor of both VEGF-receptor tyrosine kinases, was investigated for its antitumoral and antiangiogenic activity in a murine renal cell carcinoma model. After intrarenal application of the renal carcinoma cells, mice develop a primary tumor and metastases to the lung and to the abdominal lymph nodes. Daily oral therapy with PTK787/ZK 222584 at a dose of 50 mg/kg resulted in a significant decrease of 61 and 67% in primary tumors after 14 and 21 days, respectively. The occurrence of lung metastases was significantly inhibited at both time points (98% reduction and 78% reduction, respectively). After 14 days, no lymph node metastases developed in the PTK787/ZK 222584-treated group, whereas after 21 days of treatment, the lymph node metastases were reduced by 87%. Vessel density in tumor tissues, detected by immunohistochemistry with an anti-CD31 antibody, was significantly decreased by PTK787/ZK 222584. Using color Doppler imaging ultrasound, significant changes in blood flow in the tumor feeding renal artery were found under treatment with PTK787/ZK 222584. Blood flow changes correlated with changes in vessel density but not with tumor volume. The compound was well tolerated in all in vivo experiments and had no significant effects on body weight or general well-being of the animals. This was in contrast to the animals treated with the antiangiogenic agent TNP-470. s.c. therapy with 30 mg/kg TNP-470 every other day had to be discontinued after 13 days because of animal weight loss (>20%) and ataxia. These results demonstrate that PTK787/ZK 222584 is a potent inhibitor of tumor growth, metastases formation, and tumor vascularization in murine renal cell carcinoma. Furthermore, we have been able to demonstrate that color Doppler imaging ultrasound can be used to measure blood flow to a tumor and that flow correlates with vessel density. Thus, this may be a valuable noninvasive method for monitoring the effects of antiangiogenic agents such as PTK787/ZK 222584 on tumor vasculature.

Topics: Angiogenesis Inhibitors; Animals; Antibiotics, Antineoplastic; Carcinoma, Renal Cell; Cell Division; Cyclohexanes; Disease Models, Animal; Enzyme Inhibitors; Female; Kidney Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Phthalazines; Pyridines; Receptor Protein-Tyrosine Kinases; Receptors, Growth Factor; Receptors, Vascular Endothelial Growth Factor; Renal Circulation; Sesquiterpenes

A remarkable approach to a specific tumor angiogenesis model in vivo is the use of alginate implants encapsulating tumor cells. However, this previously reported approach has often been questioned because of doubts regarding the relevance of hemoglobin at the alginate implant as a parameter of vascularization. In the present investigation, we examined whether or not the use of the blood pool agents FITC-dextran of high molecular weight would significantly improve the determination of vascularization at the alginate implant. In our experiments, we found a rapid distribution of FITC-dextran within the blood circulation of mice after i.v. bolus injection. The amount of FITC-dextran within alginate implants strongly correlated with the number of LL2 carcinoma cells or B16/F10 cells encapsulated. Even a low number of 10(3) cells per alginate implant led to a significantly increased accumulation of FITC-dextran. A more than 10-fold stimulation above that of controls was found with alginate implants containing 10(4) LL2 or B16/F10 tumor cells. Using the investigational compound AGM-1470 in different treatment schedules, we found that quantification of alginate implant anglogenesis with FITC-dextran is a sensitive method for the determination of angiogenesis inhibition. In conclusion, our results demonstrated that the use of FITC-dextran enables highly sensitive, quantitative measurement of blood vessel formation by alginate implants.

Topics: Alginates; Animals; Antibiotics, Antineoplastic; Carcinoma, Lewis Lung; Carcinoma, Renal Cell; Cyclohexanes; Dextrans; Drug Carriers; Female; Fluorescein-5-isothiocyanate; Fluorescent Dyes; Glucuronic Acid; Hemostatics; Hexuronic Acids; Kidney Neoplasms; Mice; Mice, Inbred C57BL; Mice, Nude; Microspheres; Molecular Weight; Neoplasms; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes; Tumor Cells, Cultured

The effect of 0-(chloroacetyl-carbamoyl) fumagillol (TNP-470) on tumor growth and metastasis is investigated.. BALB/c mice were inoculated with Renca murine tumor and graded doses of TNP-470 were given subcutaneously every other day beginning on day 1 and ending on day 9. Tumor angiogenesis was measured quantitatively by a colorimetric assay.. TNP-470 inhibited tumor growth and prolonged the life span of Renca-bearing mice in a dose-dependent manner. Body weight-loss was not observed in the mice given less than 30 mg./kg./day. When the treatment was delayed on day 6, TNP-470 did not inhibit tumor growth, pointing to the importance of the timing of drug administration in relation to disease stage. Tumor angiogenesis was inhibited 33 to 62% of the control level by TNP-470. Furthermore, TNP-470 reduced pulmonary and hepatic metastatic foci of intravenously inoculated Renca and of the tumor inoculated in the spleen.. These data suggest that TNP-470 may be effective as a treatment of renal cell carcinoma, especially when micrometastases are involved.

Topics: Animals; Antibiotics, Antineoplastic; Carcinoma, Renal Cell; Cyclohexanes; Female; Kidney Neoplasms; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Neoplasms, Experimental; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes; Tumor Cells, Cultured

Neovascularization is critical for the growth of tumors and is mediated by physiological substances produced by the tumors. Vascular endothelial growth factor (VEGF) is one of such potent angiogenic factors. We evaluated VEGF gene expression on urinary bladder carcinoma and renal cell carcinoma by Northern blot analysis and demonstrated that VEGF was frequently overexpressed in renal cell carcinoma, in up to 67% of patients, but not in urinary bladder carcinoma. These results suggested that VEGF was produced by renal cell carcinoma and is responsible for the hypervascularity of this tumor. TNP-470, an angiogenesis inhibitor, is a new type of anticancer drug that inhibits tumor neovascularization. We evaluated the antitumor effect of TNP-470 in mice bearing B-16 melanoma or Lewis lung carcinoma. TNP-470 at a dose of 20 mg/kg body weight inhibited growth of both tumors. The degree of antitumor effect exerted by TNP-470 was greater than that of ADM (2.5 mg/kg body weight) and as great as that of MMC (2.5 mg/kg body weight). Combination of TNP-470 with MMC enhanced the antitumor effect. Monitoring of mouse body weight did not reveal any significant changes among the treatment groups, indicating that systemic toxicity of TNP-470 was not severe. These results suggested that TNP-470 was effective for the treatment of solid tumor by inhibiting its neovascularization.

Topics: Animals; Antibiotics, Antineoplastic; Carcinoma, Renal Cell; Cyclohexanes; Endothelial Growth Factors; Female; Humans; Kidney Neoplasms; Lymphokines; Male; Melanoma, Experimental; Mice; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Polymerase Chain Reaction; Sesquiterpenes; Urinary Bladder Neoplasms; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

To evaluate the antitumour effect of an angio-inhibitory drug, a synthetic analogue of fumagillin (TNP-470), on murine renal carcinoma (Renca) in vivo and in vitro.. The effect of TNP-470 on the growth of Renca cells in vitro was measured by angiogenesis assay and cell counting with dye exclusion. In the angiogenesis assay, Renca cells were injected intradermally and the number of blood vessels orientated towards the tumours was counted 3 days after tumour inoculation. To examine the effect of TNP-470 on the subcutaneous tumour growth and lung metastasis of Renca, Renca cells were injected subcutaneously or intravenously in BALB/c mice and they were treated with a subcutaneous injection every 3 days.. Dose-dependent growth inhibition in vitro was observed with 50% inhibition occurring at 600 ng/ml. Angiogenesis assay revealed that administration of TNP-470 inhibited the angiogenesis induced by Renca in a dose-dependent manner. In the subcutaneous experiment, TNP-470 decreased the growth rate of established subcutaneous tumours rather than reduced the size of the tumour. The administration of TNP-470 in mice with lung metastasis inhibited the development of metastasis of Renca without weight loss or diarrhoea.. The present study demonstrated that TNP-470 had an inhibitory effect on tumour-induced angiogenesis and a significant anti-tumour effect on Renca. This suggests that TNP-470 could be useful in the treatment of renal cell carcinoma. Further studies are needed to clarify whether TNP-470 is more effective when combined with other drugs such as interferons.

Topics: Animals; Antibiotics, Antineoplastic; Carcinoma, Renal Cell; Cell Division; Cyclohexanes; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Kidney Neoplasms; Male; Mice; Mice, Inbred BALB C; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes; Tumor Cells, Cultured