o-(chloroacetylcarbamoyl)fumagillol and Neoplasms

Topics: Allergy and Immunology; Angiogenesis Inhibitors; Animals; Cyclohexanes; History, 20th Century; History, 21st Century; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Medical Oncology; Models, Biological; Neoplasms; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes; Thalidomide

Topics: Angiogenesis Inhibitors; Combined Modality Therapy; Cyclohexanes; Drug Resistance; Neoplasms; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Receptors, Vascular Endothelial Growth Factor; Sesquiterpenes; Vascular Endothelial Growth Factor A

The tumor microenvironment is essential for tumor cell proliferation, angiogenesis, invasion, and metastasis by providing survival signals and a sanctuary site for tumor cells, by secretion of growth factors, pro-angiogenesis factors and direct adhesion molecule interactions. Our knowledge of microenvironment is only now beginning to unfold. In this review, the morphological and molecular characteristics of microenvironment in various hematological malignancies including acute lymphoblastic leukemia, acute myeloid leukemia, myelodysplastic syndrome, lymphoma, chronic lymphocytic leukemia, and multiple myeloma are summarized and the molecular mechanisms of microenvironment contributing to leukemogenesis are elucidated. We also aim to discuss the encouraging preclinical and clinical trials for treatment of hematological malignancies by targeting the tumor microenvironment. Further understanding of the signal transduction pathways between tumor cells and microenvironment will lead to the development of novel targeted therapeutic agents and more effective combination of current drugs for fighting hematological malignancies.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Cyclohexanes; Cytokines; Farnesyl-Diphosphate Farnesyltransferase; Hematologic Neoplasms; Humans; Matrix Metalloproteinase Inhibitors; Neoplasms; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes

The process of formation of new vessels from pre-existing capillaries is called angiogenesis. Angiogenesis is a complex process which involves distinct cells, soluble components and factors related to the extra-cellular matrix and which is highly important in a large variety of physiological and pathological processes in the body. Angiogenesis regulation takes place through a perfect equilibrium between the production and release of different stimulatory and inhibitory factors which vary in relation to needs and tissue types. A large number of diseases are characterized by alterations in the angiogenic process, either by an insufficiency or by excessive angiogenesis. The requirement of blood vessel proliferation for tumor growth was observed more than a century ago. Angiogenic treatment would have an indirect antitumoral action, inhibiting tumor vascularization and impairing the supply of essential nutrients for tumoral growth and development.

Topics: Angiogenesis Inhibitors; Cyclohexanes; Humans; Neoplasms; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes

Angiogenesis is the outgrowth of new vessels from pre-existing ones. Tumour growth and metastasis is dependent on angiogenesis and many stimulatory and inhibitory factors have been described which play an active role in this process. Inhibition of tumour neovasculature may be one strategy to inhibit tumour growth. Naturally occurring inhibitors of angiogenesis have been discovered and synthetic agents have been designed. Many of these inhibitors are currently being evaluated in clinical trials for the treatment of cancer. This review discusses the mechanism of action of these anti-angiogenics as well as a description of the clinical trials in which they are being evaluated.

Topics: Angiogenesis Inhibitors; Animals; Antibodies; Clinical Trials as Topic; Collagen; Cyclohexanes; Endostatins; Endothelial Growth Factors; Fatty Acids, Unsaturated; Humans; Interleukin-12; Lymphokines; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Neoplasms; O-(Chloroacetylcarbamoyl)fumagillol; Peptide Fragments; Receptor Protein-Tyrosine Kinases; Receptors, Growth Factor; Receptors, Vascular Endothelial Growth Factor; Receptors, Vitronectin; RNA, Catalytic; Sesquiterpenes; Suramin; Thalidomide; Triazoles; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

TNP-470, an analogue of fumagillin, has been shown to inhibit angiogenesis in vitro and in vivo. In 1992, TNP-470 entered clinical development for cancer as an anti-angiogenic agent. It is currently in Phase I/II trials in Kaposi's sarcoma, renal cell carcinoma, brain cancer, breast cancer, cervical cancer and prostate cancer. In early clinical reports, TNP-470 is tolerated up to 177 mg/m(2) with neurotoxic effects (fatigue, vertigo, ataxia, and loss of concentration) being the principal dose limiting toxicity (DLT). Terminal half-life values are short and have shown intermittent and intrapatient variation (range: 0.05 - 1.07 h). Recently, mechanistic studies have identified cell cycle mediators and the protein methionine aminopeptidase-2 (MetAP-2) as molecular targets of TNP-470 and fumagillin. Animal studies confirm some toxic effects on normal angiogenic processes such as the female reproductive system and wound healing, which will require caution and close monitoring in the clinic. TNP-470 is one of the first anti-angiogenic compounds to enter clinical trials, making it a valuable prototype for future trials of angiogenesis inhibitors in oncology.

Topics: Angiogenesis Inhibitors; Animals; Cyclohexanes; Humans; Neoplasms; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes

The past several years have seen demonstrable progress in the therapy of Kaposi's sarcoma (KS). Liposomal anthracyclines and paclitaxel have been found to be highly effective chemotherapeutic agents for this disease. Recent advances in our understanding of the pathogenesis of KS have led to the consideration of various new experimental agents. Two antiangiogenesis agents, TNP-470 and thalidomide, have been determined to induce some responses in KS, and others are now in early clinical trials or in preclinical development. Oral 9-cis retinoic acid has been shown to have anti-KS activity, and preliminary studies suggest that a urinary protein found in preparations of human chorionic gonadotropin also has activity. Effective anti-HIV treatment has been shown to affect the growth of KS, and the discovery of a new herpesvirus as a causative agent for KS has offered new potential targets for attack.

Topics: Administration, Oral; Alitretinoin; Anthracyclines; Antineoplastic Agents; Cyclohexanes; Humans; Immunosuppressive Agents; Liposomes; Neoplasms; O-(Chloroacetylcarbamoyl)fumagillol; Paclitaxel; Sarcoma, Kaposi; Sesquiterpenes; Thalidomide; Tretinoin

Topics: Angiostatins; Antibiotics, Antineoplastic; Antineoplastic Agents; Collagen; Cyclohexanes; Endostatins; Humans; Hydroxamic Acids; Interferons; Interleukin-12; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Peptide Fragments; Phenylalanine; Plasminogen; Sesquiterpenes; Thalidomide; Thiophenes

Neovessel formation is a pre-requisite for tumour growth and dissemination. Inhibition of angiogenesis is a promising approach for the treatment of neoplasms. In recent years, antiangiogenic drugs, such as TNP-470, have entered clinical trials. In this paper, we review the key experimental and clinical data on the role of TNP-470 in anti-tumour treatment.

Topics: Animals; Antibiotics, Antineoplastic; Cyclohexanes; Humans; Neoplasms; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes

Aberrant angiogenesis is closely involved in invasion/metastasis as well as enlargement of tumor. One recent highlight is to develop anti angiogenic drugs by targeting tumor angiogenesis. Here we describe how tumor angiogenesis is regulated and also recent topics related to angiogenic drug in clinical trials.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Cyclohexanes; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Humans; Hydroxamic Acids; Interferon-alpha; Interleukin-12; Neoplasms; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Phenylalanine; Platelet Factor 4; Polysaccharides, Bacterial; Sesquiterpenes; Thalidomide; Thiophenes; Triazines; Triazoles; Tumor Cells, Cultured

Acquisition of new blood vessels is a required step in malignant transformation, tumor growth, and metastasis. Inhibition of angiogenesis is one of the most promising new strategies for the treatment of malignant neoplasms. In recent years, several antiangiogenic compounds, including TNP-470, matrix metalloproteinase inhibitors, carboxyamidotriazole, and tecogalan sodium, have entered clinical trials. In this we review, we look at the results of early clinical trials of these agents and discuss the new angiogenesis inhibitors in preclinical development.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Clinical Trials as Topic; Cyclohexanes; Humans; Neoplasms; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes

Recent studies on angiogenesis in human solid tumors have underlined its importance as therapeutic target. In particular, of interest is to suppress the function of several positive regulators including vascular endothelial growth factors (VEGF), basic fibroblast growth factor and thymidine phosphorylase, because they are evident to be responsible for the promotion of neovascularization in a variety of tumor types. In this review, we picked up VEGF, probably one of most promising target, and discuss about the therapeutic tools for controlling VEGF function in human tumors.

Topics: Antibiotics, Antineoplastic; Cyclohexanes; Endothelial Growth Factors; Humans; Lymphokines; Neoplasms; 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

Inhibition of angiogenesis or preventing the outgrowth of new blood vessels towards a tumor is one of the most promising areas of anticancer drug development. Several angiogenesis inhibitors are now on the verge of being tested in clinical trials. This review discusses possible applications of inhibitors of angiogenesis and whether the current methodologies for testing novel anticancer drugs are appropriate to evaluate the efficacy of inhibitors of angiogenesis.

Topics: Angiostatins; Cyclohexanes; Endothelial Growth Factors; Humans; Integrins; Lymphokines; Metalloendopeptidases; Neoplasm Recurrence, Local; Neoplasms; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Peptide Fragments; Plasminogen; Platelet Factor 4; Sesquiterpenes; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Topics: Animals; Anti-Bacterial Agents; Antineoplastic Agents; Cell Hypoxia; Chick Embryo; Combined Modality Therapy; Cyclohexanes; Drug Therapy, Combination; Humans; Mice; Minocycline; Neoplasms; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Rabbits; Rats; Sesquiterpenes

Topics: Animals; Antibiotics, Antineoplastic; Cattle; Cells, Cultured; Clinical Trials as Topic; Combined Modality Therapy; Cyclohexanes; Drug Therapy, Combination; Endothelium, Vascular; Humans; Macaca mulatta; Mice; Neoplasms; Neovascularization, Pathologic; Neovascularization, Physiologic; O-(Chloroacetylcarbamoyl)fumagillol; Rats; Sesquiterpenes

Preclinical studies have demonstrated a synergistic effect with the angiogenesis inhibitor TNP-470 and several cytotoxic agents. A recent clinical trial with the combination of paclitaxel and TNP-470 has shown promising effects. The present study was designed to determine the toxicity and pharmacokinetics of carboplatin in combination with TNP-470 in comparison with the doublet regimen of paclitaxel and carboplatin in patients with solid tumors.. Enrolled in the study were 17 patients with lung (11), head/neck (3), sarcoma (2) and thymoma (1). The patients received intravenous paclitaxel and carboplatin on day 1 followed by TNP-470 (60 mg/m(2) i.v. over 1 h administered thrice weekly on Monday, Wednesday, and Friday). Each cycle of therapy consisted of 3 weeks. The initial cohort of three patients received carboplatin at AUC 5 mg/ml x min. No dose-limiting toxic effects occurred, thus the subsequent cohort received carboplatin at AUC 6 mg/ml x min. In addition to toxicity, the pharmacokinetics of carboplatin were evaluated, and tumor response and patient survival rates were assessed.. The administered regimen of paclitaxel (225 mg/m(2) i.v. over 3 h) and carboplatin (AUC 6 mg/ml x min i.v. over 1 h) on day 1 followed by TNP-470 (60 mg/m(2) i.v. over 1 h administered thrice weekly on Monday, Wednesday, and Friday) was defined as both the maximum tolerated and optimal dose. Hematological toxic effects were similar to those expected with the chemotherapy doublet. All neurocognitive impairments were graded as mild to moderate and reversed after discontinuation of TNP-470 administration. No alterations in the pharmacokinetic disposition of carboplatin were noted. Overall, the median survival duration was 297 days. Four patients (24%) had a partial response, and eight (47%) had stable disease.. The combination of TNP-470, paclitaxel, and carboplatin is a reasonably well tolerated regimen. Further randomized studies of TNP-470 with this doublet regimen are now warranted for non-small-cell lung carcinoma and other solid tumors.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cyclohexanes; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasms; O-(Chloroacetylcarbamoyl)fumagillol; Paclitaxel; Sesquiterpenes

A Phase I study of angiogenesis inhibitor TNP-470 was conducted in patients with advanced cancer. TNP-470 (25-235 mg/m2) was administered i.v. over 4 h once a week to patients who had solid tumors refractory to the best available treatment or with a high risk of recurrence and who had normal renal, hepatic, and hematological function and no evidence of coagulopathy. The aims of the study were to determine the maximum tolerated dose, dose-limiting toxicities (DLTs), and the pharmacokinetics of TNP-470 given on a once-weekly schedule. Thirty-six patients, ages 23-75 (median, 54 years), with an Eastern Cooperative Oncology Group performance status of 0-2 were treated. The number of patients at each dose level (mg/m2) were 6 (25), 3 (50), 3 (75), 3 (100), 3 (133), 12 (177), and 6 (235). The principal toxicities of TNP-470 were dizziness, lightheadedness, vertigo, ataxia, decrease in concentration and short-term memory, confusion, anxiety, and depression, which occurred at doses of 133, 177, and 235 mg/m2. Two patients treated at 235 mg/m2 experienced DLT in the form of grade III cerebellar neurotoxicity after 6 weeks of treatment. Overall, these neurological symptoms were dose-related, had an insidious onset, progressively worsened with treatment, and resolved completely within 2 weeks of stopping the drug. One patient with malignant melanoma had stabilization of the previously growing disease for 27 weeks while on the treatment. Two patients, one with adenocarcinoma of the colon and the other with a soft tissue sarcoma, had no clinically detectable disease but were at high risk for recurrence at the initiation of treatment and received 13 months and > 3 years of treatment, respectively, with no evidence of disease recurrence. The remaining patients had progression of their disease after 1-6 months of treatment. The mean plasma half-life (t(1/2)) of TNP-470 and its principal metabolite, AGM-1883, were extremely short (harmonic mean, t(1/2) of 2 and 6 min, respectively) with practically no drug detectable in the plasma by 60 min after the end of the infusion. MII, an inactive metabolite, had a considerably longer t(1/2) of approximately 2.6 h. Mean peak TNP-470 concentrations were > or = 400 ng/ml at doses > or = 177 mg/m2. On the basis of this study, the maximum tolerated dose of TNP-470 administered on a weekly schedule was 177 mg/m2 given i.v over 4 h. The principal DLT was neurotoxicity, which appeared to be dose-related and was completely reversible. On t

Topics: Adult; Aged; Antibiotics, Antineoplastic; Central Nervous System; Cerebellar Ataxia; Confusion; Cyclohexanes; Dose-Response Relationship, Drug; Drug Evaluation; Female; Humans; Male; Memory; Middle Aged; Neoplasms; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes; Vertigo

The purpose of the present study was to develop an advanced method of anti-angiogenic chemoembolization to target morphological vascular heterogeneity in tumors and further the therapeutic efficacy of cancer treatment. This new chemoembolization approach was designed using resorbable calcium-phosphate ceramic microspheres (CPMs), in a mixture of three different sizes, which were loaded with an anti-angiogenic agent to target the tumor vasculature in highly angiogenic solid tumors in humans in vivo. The human uterine carcinosarcoma cell line, FU-MMT-3, was used in this study because the tumor is highly aggressive and exhibits a poor response to radiotherapy and chemotherapeutic agents that are in current use. CPMs loaded with TNP-470, an anti-angiogenic agent, were injected into FU-MMT-3 xenografts in nude mice three times per week for 8 weeks. The treatment with TNP-470-loaded CPMs of three different diameters achieved a greater suppression of tumor growth in comparison to treatment with single-size TNP-470-loaded CPMs alone, and the control. Severe loss of body weight was not observed in any mice treated with any size of TNP-470-loaded CPMs. These results suggest that treatment with a mixture of differently-sized anti-angiogenic CPMs might be more effective than treatment with CPMs of a single size. This advanced chemoembolization method, which incorporated an anti-angiogenic agent to target the morphological vascular heterogeneity of tumors may contribute to effective treatment of locally advanced or recurrent solid tumors.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Calcium Phosphates; Ceramics; Chemoembolization, Therapeutic; Crystallization; Cyclohexanes; Humans; Mice, Nude; Microscopy, Electron, Scanning; Microspheres; Neoplasms; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes; Xenograft Model Antitumor Assays

An increasingly appreciated focus of carcinogenesis research is on mechanisms governing tumor growth after the fact of cancer cell creation. Of particular interest are dynamical interactions between tumor and host cell populations that can themselves strongly impact the fate of established cancer lesions. Regardless of tumor type, all cancers face the common problem of having to breach the barrier of angiogenic competency in order to advance from a microscopic lesion to symptomatic disease. If pre-angiogenic tumor cells are held in dormancy due to cell cycle arrest, this will postpone the need to traverse this higher-level barrier. On the other hand, the barrier itself may prove limiting to a tumor at its diffusion-limited size, creating a population-level dormancy characterized by balanced proliferation and cell death. In both cases of dormancy, the "angiogenic switch" has not yet occurred. We here describe and mathematically quantify an underappreciated third dormancy state defined by an angiogenic balance following the angiogenic switch. In this state we term "post-vascular dormancy," a tumor has attained angiogenic competency, but again demonstrates balanced proliferation and cell death because ambient pro- and anti-angiogenic influences are offsetting. Interestingly, autopsies have shown virtually all of us carry latent tumors in pre- or post-vascular states, many of which lie under the threshold of routine clinical detection. We show how, in the post-vascular case, tumor latency can arise from an elaborate mechanism of self-controlled growth, mediated through the tumor-vascular interaction. Underlying this observation is the finding that a tumor produces both angiogenesis stimulators and inhibitors, with the latter having greater influence, both locally and systemically, as the tumor grows-a mechanism we hypothesize is an aberrant co-option of normal organogenic regulation. That a tumor can limit its own growth raises the prospect that chronic therapies aimed at suppressing this tumor-host dynamic may compare favorably to current strategies which often yield favorable short-term responses but fail to deliver long-term tumor suppression.

Topics: Angiogenesis Inducing Agents; Angiogenesis Inhibitors; Animals; Cell Cycle Checkpoints; Cell Death; Cyclohexanes; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Logistic Models; Metabolic Clearance Rate; Mice; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes; Tumor Cells, Cultured; Tumor Microenvironment

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Cyclohexanes; Humans; Neoplasms; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes; Treatment Outcome

Tumor escape from immunity, as well as the failure of several anti-cancer vaccination and cellular immunotherapy approaches, is suggested to be due to the angiogenesis-mediated suppression of endothelial cell (EC) adhesion molecules involved in leukocyte-vessel wall interactions. We hypothesized that inhibition of angiogenesis would overcome this escape from immunity. We investigated this in vivo by means of intravital microscopy and ex vivo by immunohistochemistry in two mouse tumor models. Angiogenesis inhibitors anginex, endostatin, and angiostatin, and the chemotherapeutic agent paclitaxel were found to significantly stimulate leukocyte-vessel wall interactions by circumvention of EC anergy in vivo, i.e., by the up-regulation of endothelial adhesion molecules in tumor vessels. This was confirmed by in vitro studies of cultured EC at the protein and mRNA levels. The new angiostatic designer peptide anginex was most potent at overcoming EC anergy; the enhanced leukocyte-vessel interactions led to an increase in the numbers of tumor infiltrating leukocytes. While anginex inhibited tumor growth and microvessel density significantly, the amount of infiltrated leukocytes (CD45), as well as the number of CD8+ cytotoxic T lymphocytes, was enhanced markedly. The current results suggest that immunotherapy strategies can be improved by combination with anti-angiogenesis.

Topics: Angiostatins; Animals; Antineoplastic Agents; Cell Line, Tumor; Clonal Anergy; Cyclohexanes; Cyclophosphamide; Down-Regulation; Endostatins; Endothelial Cells; Endothelium; Humans; Intercellular Adhesion Molecule-1; Leukocytes; Mice; Neoplasms; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Paclitaxel; Peptides; Proteins; Sesquiterpenes; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

Angiogenesis inhibitors, such as TNP-470 and the nontoxic HPMA copolymer-TNP-470 (caplostatin), are emerging as a class of anticancer drugs. We report that TNP-470 and caplostatin inhibit vascular hyperpermeability of tumor blood vessels as well as that induced in mouse skin by different mediators. Treatment with TNP-470 or angiostatin for 3 days was sufficient to reduce permeability of tumor blood vessels, delayed-type hypersensitivity, and pulmonary edema induced by IL-2. TNP-470 also inhibited VPF/VEGF-induced phosphorylation of VEGFR-2, calcium influx, and RhoA activation in endothelial cells. These results identify an activity of TNP-470, that of inhibiting vessel hyperpermeability. This activity likely contributes to TNP-470's antiangiogenic effect and suggests that caplostatin can be used in the treatment of cancer and inflammation.

Topics: Angiogenesis Inhibitors; Angiostatins; Animals; Calcium; Capillaries; Capillary Permeability; Cell Movement; Cyclohexanes; Endothelial Cells; Female; Hypersensitivity, Delayed; Interleukin-2; Male; Mice; Mice, Inbred C57BL; Mice, SCID; Mitogen-Activated Protein Kinases; Neoplasms; O-(Chloroacetylcarbamoyl)fumagillol; Pulmonary Edema; rhoA GTP-Binding Protein; Sesquiterpenes; Skin; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

TNP-470 (AGM-1470), an analogue of fumagillin, was one of the first molecules proposed to have antiangiogenic properties. This concept was based on its ability to inhibit both endothelial proliferation in vitro and tumor growth in vivo in a number of xenograft models. Yet, subsequent investigations indicated that the biochemical activities associated with TNP-470 are not selective for endothelial cells. Moreover, recent evidence suggests that this agent inhibits tumor growth in vivo, but without a corresponding decrease in angiogenesis. Therefore, we performed a detailed comparison of TNP-470 to a validated antiangiogenic agent, a VEGF inhibitor termed VEGF-Trap, using a xenograft model of Wilms tumor. Treatment with TNP-470 for 5 weeks significantly suppressed xenograft growth (83%). Surprisingly, this inhibition was not associated with a decrease in angiogenesis, but instead with an increase in tiny neovessels. To determine whether this was a direct effect of TNP-470 on tumor vessels, we examined its effect in a short-term assay using large tumors with established vasculature. In contrast to treatment with VEGF-Trap, which led to rapid vessel regression and tumor hypoxia, tumors exposed to TNP-470 for 1 day displayed increased capillary sprouting, with significantly increased microvessel density, vessel length, and branch points. TNP-470 did not induce tumor hypoxia as demonstrated by minimal pimonidazole staining and VEGF expression. TNP-470 did, however, cause a marked increase in apoptosis of tumor cells. Our results indicate that the antitumor effects of TNP-470 cannot be attributed to prevention of neoangiogenesis, but instead to its direct action on tumor cells.

Topics: Angiogenesis Inhibitors; Angiography; Animals; Antibiotics, Antineoplastic; Apoptosis; Capillaries; Cell Line, Tumor; Cyclohexanes; Fluorescein; Humans; Hypoxia; Immunohistochemistry; In Situ Hybridization; In Situ Nick-End Labeling; Lectins; Mice; Mice, Nude; Microcirculation; Neoplasm Transplantation; Neoplasms; Neovascularization, Pathologic; Nitroimidazoles; O-(Chloroacetylcarbamoyl)fumagillol; Radiation-Sensitizing Agents; Sesquiterpenes; Vascular Endothelial Growth Factor A; Wilms Tumor

The availability of noninvasive techniques to detect the effects of antiangiogenic agents is critically important for optimizing treatment of cancer with these agents. Magnetic resonance imaging (MRI) is one such noninvasive technique that is routinely used clinically.. In this study, we have evaluated the use of MRI of the intravascular contrast agent albumin-GdDTPA to detect the effects of the antiangiogenic agent TNP-470 on the vascular volume and permeability of the MatLyLu prostate cancer model.. TNP-470-treated tumors demonstrated a significant decrease of vascular volume, as well as a significant reduction in vascular and permeable regions, compared with volume-matched control tumors. Although the fractional volume of permeable regions in the tumor decreased, the average value of tumor permeability did not decrease significantly. This was attributable to increase in permeability in some regions of the tumor. These regions were mostly associated with low vascular volume. ELISA assays of control and treated MatLyLu tumors also detected a significant increase of vascular endothelial growth factor in the TNP-470-treated tumors.. MRI detected significant changes in tumor vascular characteristics after treatment with TNP-470.

Topics: Angiogenesis Inhibitors; Animals; Antibiotics, Antineoplastic; Contrast Media; Cyclohexanes; Endothelial Growth Factors; Enzyme-Linked Immunosorbent Assay; Intercellular Signaling Peptides and Proteins; Lymphokines; Magnetic Resonance Imaging; Male; Neoplasms; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Prostatic Neoplasms; Rats; Sesquiterpenes; Time Factors; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Cyclohexanes; Humans; Mice; Neoplasms; Neoplasms, Experimental; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; 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

Topics: Antineoplastic Agents; Cyclohexanes; Drugs, Investigational; Endothelial Growth Factors; Humans; Interferon-alpha; Lymphokines; Neoplasms; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Polysaccharides, Bacterial; Sesquiterpenes; Thalidomide; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Topics: Antibiotics, Antineoplastic; Cyclohexanes; Humans; Neoplasms; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Prognosis; Sesquiterpenes