o-(chloroacetylcarbamoyl)fumagillol and Prostatic-Neoplasms

Metastatic prostate cancer is one of the leading causes of cancer death in men. Although initially responsive to hormone therapy, it eventually progresses in almost all patients. For this reason, there has been a search for novel agents to use in the fight against androgen-independent prostate cancer. Antiangiogenesis is a relatively new antitumor strategy that has been employed in the treatments of many malignancies. As prostate cancer is likely dependent on angiogenesis for its growth and progression, it would logically serve as a good target for this modality. Initially met with great enthusiasm, antiangiogenic drugs have seen only limited success when used as single agents. This has been attributed to many possible etiologies including lack of cytotoxicity and use in situations of large tumor burden. In order to overcome these problems, many investigators are combining antiangiogenic agents with more traditional cytotoxic chemotherapy regimens in hope of augmenting the effects of either drug alone. This article will review the background of angiogenesis inhibition and the use of such combinations in metastatic prostate cancer.

Topics: Angiogenesis Inhibitors; Anti-Bacterial Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Clinical Trials as Topic; Cyclohexanes; Humans; Male; Minocycline; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Paclitaxel; Prostatic Neoplasms; Sesquiterpenes

PSA has been a valuable tool in enhancing our understanding of the prevalence and virulence of prostate cancer. PSA also has contributed to the understanding of important phenomena related to the androgen regulation of the cancer; however, it has not been useful in detecting some forms of androgen-independent (neuroendocrine) progression and is of limited prognostic value in androgen-independent prostate cancer. PSA also has been valuable in the accelerated development of therapies for prostate cancer; however, it must be used cautiously for this purpose, because it may not reflect the most relevant clone. In addition, some agents may directly affect PSA release independent of their antitumor activity. Most importantly, before PSA is adopted as a surrogate end point in clinical trials in prostate cancer, it must be prospectively validated. Future studies must focus on the development of prospective serologic tumor markers that can predict virulence of disease and to reflect androgen-independent progression.

Topics: Androgen Antagonists; Antineoplastic Agents; Cyclohexanes; Humans; Male; O-(Chloroacetylcarbamoyl)fumagillol; Orchiectomy; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms; Sesquiterpenes; Suramin

Clinical and laboratory observations support the view that angiogenesis is necessary for prostate cancer progression. The angiogenesis inhibitor TNP-470 has demonstrated in vivo antitumor activity in a series of clinical models. To evaluate a possible therapeutic clinical value, we conducted a Phase I dose escalation trial of alternate-day i.v. TNP-470 in 33 patients with metastatic and androgen-independent prostate cancer. The patients were evaluated during therapy for evidence of neurological toxic effects. An assay of endothelial and vascular proliferation "markers" and a sequential assay of serum prostate-specific antigen concentration were performed. The effects of TNP-470 could be evaluated in 32 of the 33 patients. The maximum tolerated dose was 70.88 mg/m(2) of body surface area. The dose-limiting toxic effect was a characteristic neuropsychiatric symptom complex (anesthesia, gait disturbance, and agitation) that resolved upon cessation of therapy. The times to clinical recovery of neurological side effects were 6, 8, and 14 weeks. No definite antitumor activity of TNP-470 was observed; however, transient stimulation of the serum prostate-specific antigen concentration occurred in some of the patients treated. Additional studies of TNP-470 should be conducted using an alternate-day i.v. injection of 47.25 mg/m(2) body surface area and should focus on understanding and overcoming the neurological toxic effects. In addition, valid intermediate end points that reflect the status of tumor-associated neovascularity are needed to facilitate effective development of treatment strategies.

Topics: Aged; Androgens; Angiogenesis Inhibitors; Blood Glucose; Bone and Bones; Communicable Diseases; Cyclohexanes; Digestive System; Fibroblast Growth Factors; Humans; Kinetics; Liver; Male; Middle Aged; O-(Chloroacetylcarbamoyl)fumagillol; Pain; Prostate-Specific Antigen; Prostatic Neoplasms; Sesquiterpenes; Thrombomodulin

Aging is considered one of the main predisposing factors for the development of prostate malignancies. Angiogenesis is fundamental for tumor growth and its inhibition represents a promising therapeutic approach in cancer treatment. Thus, we sought to determine angiogenic responses and the effects of antiangiogenic therapy in the mouse prostate during late life, comparing these findings with the prostatic microenvironment in the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model.. Male mice (52 week-old FVB) were submitted to treatments with SU5416 (6 mg/kg; i.p.) and/or TNP-470 (15 mg/kg; s.c.). Finasteride was administered (20 mg/kg; s.c.), alone or in association to both inhibitors. The dorsolateral prostate was collected for VEGF, HIF-1α, FGF-2 and endostatin immunohistochemical and Western Blotting analyses and for microvessel density (MVD) count.. Senescence led to increased MVD and VEGF, HIF-1α and FGF-2 protein levels in the prostatic microenvironment, similarly to what was observed in TRAMP mice prostate. The angiogenic process was impaired in all the treated groups, demonstrating significantly decreased MVD. Antiangiogenic and/or finasteride treatments resulted in decreased VEGF and HIF-1α levels, especially following TNP-470 administration, either alone or associated to SU5416. The combination of these agents resulted in increased endostatin levels, regardless of the presence of finasteride.. Prostatic angiogenesis stimulation during senescence favored the development of neoplastic lesions, considering the pro-angiogenic microenvironment as a common aspect also observed during cancer progression in TRAMP mice. The combined antiangiogenic therapy was more efficient, leading to enhanced imbalance towards angiogenic inhibition in the organ. Finally, finasteride administration might secondarily upregulate the expression of pro-angiogenic factors, pointing to the harmful effects of this therapy.

Topics: 5-alpha Reductase Inhibitors; Adenocarcinoma; Angiogenesis Inhibitors; Animals; Blotting, Western; Cyclohexanes; Disease Models, Animal; Endostatins; Fibroblast Growth Factor 2; Finasteride; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Indoles; Male; Mice; Mice, Transgenic; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Prostatic Neoplasms; Pyrroles; Sesquiterpenes; Tumor Microenvironment; Vascular Endothelial Growth Factor A

Therapy-induced stimulation of angiogenic molecules can promote tumor angiogenesis leading to enhanced tumor growth and cancer metastasis. Several standard and emerging therapies, such as radiation and photodynamic therapy (PDT), can induce angiogenic molecules, thus limiting their effectiveness. PDT is approved for the treatment of several cancers; however, its induction of vascular endothelial growth factor (VEGF) creates conditions favorable to enhanced tumor growth and metastasis, therefore mitigating its cytotoxic and antivascular effects. This is the first report showing that subcurative PDT in an orthotopic model of prostate cancer (LNCaP) increases not only VEGF secretion (2.1-fold) but also the fraction of animals with lymph node metastases. PDT followed by administration of an antiangiogenic agent, TNP-470, abolished this increase and reduced local tumor growth. On the other hand, administration of TNP-470 before PDT was less effective at local tumor control. In addition, animals in all groups, except in the PDT + TNP-470 group, had a weight loss of >3 g at the time of sacrifice; the weight of the animals in the PDT + TNP-470 group did not change. The significant reduction (P < 0.05) in tumor weight and volume observed between the PDT + TNP-470 group and the control group suggests that the combination of PDT and antiangiogenic treatment administered in the appropriate sequence was not only more effective at controlling local tumor growth and metastases but also reduced disease-related toxicities. Such molecular response-based combinations merit further investigations as they enhance both monotherapies and lead to improved treatment outcomes.

Topics: Angiogenesis Inhibitors; Animals; Cell Growth Processes; Cell Line, Tumor; Combined Modality Therapy; Cyclohexanes; Humans; Lymphatic Metastasis; Male; Mice; Mice, SCID; Neoplasm Metastasis; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Photochemotherapy; Prostatic Neoplasms; Sesquiterpenes; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

TNP-470, a potent inhibitor of angiogenesis, was reported to synergistically enhance the antitumor effects of cytotoxic agents. The objective of this study was to evaluate the effectiveness of combined treatment with TNP-470 and docetaxel both in vitro and in vivo using androgen-independent human prostate cancer PC-3 cells. The in vitro growth-inhibitory and apoptotic effects of docetaxel and/or TNP-470 on PC-3 cells were assessed using MTT and TUNEL assays. The combined effect of docetaxel and TNP-470 therapy after subcutaneous and orthotopic injection of PC-3 cells into athymic nude mice was evaluated. In vivo effects of this combined regimen on PC-3 tumors were analyzed by the TUNEL assay and immunohistochemical staining of CD31 to quantify microvessel density (MVD). Combined treatment with TNP-470 and docetaxel synergistically inhibited PC-3 cell growth in vitro through the enhanced induction of apoptotic cell death compared with treatment with either agent alone, a result explained, at least in part, by the down-regulation as well as phosphorylation of potential anti-apoptotic genes, Bcl-2 and Bcl-XL. Combined treatment with TNP-470 and docetaxel synergistically suppressed subcutaneous PC-3 tumor growth compared with treatment with either agent alone. Furthermore, this combined regimen significantly inhibited orthotopic PC-3 tumor growth and reduced the incidence of lymph node metastasis. Immunohistochemical analysis of the subcutaneous tumor after each treatment demonstrated that administration of docetaxel as well as TNP-470 significantly induced apoptotic cell death; in contrast, a significant reduction in MVD was observed only after TNP-470. These findings suggest that docetaxel and TNP-470 act synergistically to inhibit PC-3 tumor growth and metastasis, by enhancing apoptosis and suppressing angiogenesis.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents, Phytogenic; Apoptosis; Cyclohexanes; Docetaxel; Drug Interactions; Humans; Male; Neoplasm Metastasis; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Prostatic Neoplasms; Sesquiterpenes; Taxoids; Tumor Cells, Cultured

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

We have previously shown that C-CAM1-based gene therapy effectively suppressed prostate tumor growth in nude mice xenograft models. In this study, we examined the effects of combining C-CAM1-based therapy and TNP-470, a potent angiogenesis inhibitor, on prostate cancer in a xenografted tumor model. The direct cytotoxic effects of Ad-C-CAM1 (recombinant adenovirus containing C-CAM1 cDNA) and TNP-470 on DU145 cells in vitro were determined by microculture tetrazolium assay. The in vivo antitumor effects of either agent alone were studied in a DU145 xenografted tumor model. Cells were infected with Ad-C-CAM1 or the control virus at multiplicities of infection (m.o.i.) of 5 or 10 and then inoculated onto nude mice 48 h later. TNP-470 (0, 17 or 35 mg/kg) was given 15, 17 and 19 days after inoculation. Combined treatments in vivo were carried out to determine whether there were synergistic antitumor effects. Both Ad-C-CAM1 and the control virus were minimally toxic to DU145 in vitro. There was evident dose-dependent suppression of xenografted tumor growth by either Ad-C-CAM1 or TNP-470. By the median-effect analysis, combination of the two agents generated strong synergistic antitumor effects as shown by marked tumor suppression as compared to either treatment alone. The novel strategy may have clinical implications for the treatment of prostate cancer.

Topics: Adenosine Triphosphatases; Angiogenesis Inhibitors; Animals; Antigens, CD; Carcinoembryonic Antigen; Cell Adhesion Molecules; Cell Survival; Combined Modality Therapy; Cyclohexanes; Dose-Response Relationship, Drug; Genetic Therapy; Glycoproteins; Male; Mice; Mice, Inbred BALB C; Mice, Nude; O-(Chloroacetylcarbamoyl)fumagillol; Prostatic Neoplasms; Sesquiterpenes; Tumor Cells, Cultured

Tumors commonly outgrow their blood supply, thereby creating hypoxic conditions, which induce apoptosis and increase expression of angiogenic growth factors. The bcl-2 oncogene inhibits apoptosis induced by a variety of stimuli, including hypoxia. On the basis of bcl-2's role in regulating apoptosis in response to hypoxia, we hypothesized that this oncogene might affect other responses to hypoxia, such as the expression of angiogenic growth factors.. Three prostate carcinoma cell lines, PC3, LNCaP, and DU-145, were stably transfected with a bcl-2 complementary DNA (cDNA), and transfectants were analyzed in vitro for the expression of angiogenic factors after exposure to either normoxic (19% O(2)) or hypoxic (1% O(2)) conditions. The in vivo angiogenic potential of the transfected cells was determined by analyzing vessel density in xenografts derived from them and by measuring the ability of these xenografts to induce neovascularization when implanted in mouse corneal micropockets. Statistical tests were two-sided.. When exposed to hypoxic conditions, prostate carcinoma cells overexpressing bcl-2 expressed statistically significantly higher levels of vascular endothelial growth factor (VEGF), an angiogenic factor, than control-transfected cells (P = .001 for PC3, P = .04 for DU-145 after 48 hours). This effect of bcl-2 was independent of its antiapoptotic activity because increased expression of VEGF was detected in PC3 cells overexpressing bcl-2 even though PC3 cells are inherently resistant to hypoxia-induced apoptosis. In vivo, xenograft tumors derived from the bcl-2-overexpressing prostate carcinoma cell lines displayed increased angiogenic potential and grew more aggressively than tumors derived from the control cell lines (P =.03 for PC3). Treatment of bcl-2-overexpressing and control tumors with the antiangiogenic drug TNP-470 neutralized the aggressive angiogenesis in bcl-2-overexpressing tumors (P = .04 for PC3, P = .004 for DU-145) and the moderate angiogenesis in control tumors (P = .01 for PC3, P = .05 for DU-145), resulting in similar growth rates for both tumors.. bcl-2 may play a dual role in tumorigenesis by suppressing apoptosis and by stimulating angiogenesis.

Topics: Angiogenesis Inducing Agents; Angiogenesis Inhibitors; Animals; Antibiotics, Antineoplastic; Apoptosis; Blotting, Western; Cell Hypoxia; Cornea; Cyclohexanes; Endothelial Growth Factors; Enzyme-Linked Immunosorbent Assay; Eye Neoplasms; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Lymphokines; Male; Mice; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Platelet Endothelial Cell Adhesion Molecule-1; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; Sesquiterpenes; Transcription Factors; Transfection; Transplantation, Heterologous; Tumor Cells, Cultured; Up-Regulation; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Topics: Antibiotics, Antineoplastic; Cyclohexanes; Humans; Male; O-(Chloroacetylcarbamoyl)fumagillol; Prostatic Neoplasms; Sesquiterpenes

Inhibitory effects of TNP-470, a synthetic analogue of the antibiotic fumagillin secreted by Aspergillus fumigatus, were studied with respect to growth and lung metastasis of the hormone-independent rat prostatic carcinoma cell line AT6.3.. Rat prostatic carcinoma AT6.3 cells were implanted in nude mice subcutaneously. Antimetastatic and growth-inhibitory effects of TNP-470 in vivo were examined 3 weeks after inoculation of AT6.3 cells. Direct growth-inhibitory effect was examined by MTT assay in vitro.. TNP-470 inhibited the growth of AT6.3 cells in vitro. Subcutaneously injected TNP-470 markedly reduced numbers and individual size of lung metastases from AT6.3 cells inoculated percutaneously or intravenously into male BALB/c-nu/nu mice.. This agent, which acts as an angiogenesis inhibitor, may prove to be clinically useful in preventing metastasis of hormone-independent prostatic cancer.

Topics: Animals; Antibiotics, Antineoplastic; Cell Division; Cyclohexanes; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Prostatic Neoplasms; Rats; Sesquiterpenes; Tumor Cells, Cultured

The angiogenesis inhibitor O-(chloroacetyl-carbamoyl)fumagillol (TNP-470) showed antitumor activity in three human cancer xenograft systems. TNP-470 potently inhibited the tumor growth of hormone-independent prostate cancer PC-3 cells and breast cancer MDA-MB-231 cells dose dependently at weekly s.c. doses of 50-200 mg/kg with maximum inhibition of 96 and 88% (tumor growth, 4 and 12% of that in the respective control). In experiments of combination therapy with chemotherapeutic agents, the combination of TNP-470 (100 mg/kg) and cisplatin (5 mg/kg) showed an additive antitumor effect (from treated versus control, 38 and 22% to 5%) against PC-3 carcinoma. 5-Fluorouracil and Adriamycin alone did not significantly inhibit MDA-MB-231 tumor growth (treated versus control, 131 and 64%, respectively). TNP-470 also inhibited tumor growth of WiDr colon cancer; although the inhibition was less marked (treated versus control, 39%) than that observed with the hormone-independent cancers used in this study. In an in vitro study, all the cell lines tested were considerably insensitive to TNP-470 in monolayer cultures (50% inhibitory concentration, approximately 5 micrograms/ml), whereas TNP-470 inhibited the anchorage-independent growth of PC-3 and MDA-MB-231 cells (50% inhibitory concentration, 0.05 and 470 ng/ml, respectively). The inhibitory activity of TNP-470 against anchorage-independent growth correlated well with the in vivo antitumor activity among the cell lines tested. Thus, this inhibitory action may partly contribute to the potent antitumor activity of the angiogenesis inhibitor TNP-470, at least in the case of PC-3 and MDA-MB-231. These results suggest that hormone-independent prostate and breast cancers may be appropriate target diseases for TNP-470 clinical trials.

Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Division; Cell Line; Cell Survival; Cisplatin; Cyclohexanes; Dose-Response Relationship, Drug; Doxorubicin; Drug Synergism; Fluorouracil; Humans; Male; Mice; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Prostatic Neoplasms; Sesquiterpenes; Transplantation, Heterologous; Tumor Cells, Cultured