The major cholesterol metabolite cholestane-3ß,5α,6ß-triol functions as an endogenous neuroprotectant.

Overstimulation of NMDA-type glutamate receptors is believed to be responsible for neuronal death of the CNS in various disorders, including cerebral and spinal cord ischemia. However, the intrinsic and physiological mechanisms of modulation of these receptors are essentially unknown. Here we report that cholestane-3ß,5α,6ß-triol (triol), a major metabolite of cholesterol, is an endogenous neuroprotectant and protects against neuronal injury both in vitro and in vivo via negative modulation of NMDA receptors. Treatment of cultured neurons with triol protects against glutamate-induced neurotoxicity, and administration of triol significantly decreases neuronal injury after spinal cord ischemia in rabbits and transient focal cerebral ischemia in rats. An inducible elevation of triol is associated with ischemic preconditioning and subsequent neuroprotection in the spinal cord of rabbits. This neuroprotection is effectively abolished by preadministration of a specific inhibitor of triol synthesis. Physiological concentrations of triol attenuate [Ca(2+)]i induced by glutamate and decrease inward NMDA-mediated currents in cultured cortical neurons and HEK-293 cells transiently transfected with NR1/NR2B NMDA receptors. Saturable binding of [(3)H]triol to cerebellar granule neurons and displacement of [(3)H]MK-801 binding to NMDA receptors by triol suggest that direct blockade of NMDA receptors may underlie the neuroprotective properties. Our findings suggest that the naturally occurring oxysterol, the major cholesterol metabolite triol, functions as an endogenous neuroprotectant in vivo, which may provide novel insights into understanding and developing potential therapeutics for disorders in the CNS.

The tumor-suppressor cholesterol metabolite, dendrogenin A, is a new class of LXR modulator activating lethal autophagy in cancers.

Dendrogenin A (DDA) is a mammalian cholesterol metabolite recently identified that displays tumor suppressor properties. The discovery of DDA has revealed the existence in mammals of a new metabolic branch in the cholesterol pathway centered on 5,6α-epoxycholesterol and bridging cholesterol metabolism with histamine metabolism. Metabolic studies showed a drop in DDA levels in cancer cells and tumors compared to normal cells, suggesting a link between DDA metabolism deregulation and oncogenesis. Importantly, complementation of cancer cells with DDA induced 1) cancer cell re-differentiation, 2) blockade of 6-oxo-cholestan-3ß,5α-diol (OCDO) production, an endogenous tumor promoter and 3) lethal autophagy in tumors. Importantly, by binding the liver X receptor (LXR), DDA activates the expression of genes controlling autophagy. These genes include NR4A1, NR4A3, LC3 and TFEB. The canonical LXR ligands 22(R)hydroxycholesterol, TO901317 and GW3965 did not induce these effects indicating that DDA delineates a new class of selective LXR modulator (SLiM). The induction of lethal autophagy by DDA was associated with the accumulation in cancer cells of lysosomes and of the pro-lysosomal cholesterol precursor zymostenol due to the inhibition of the 3ß-hydroxysteroid-Δ8Δ7-isomerase enzyme (D8D7I). The anti-cancer efficacy of DDA was established on different mouse and human cancers such as breast cancers, melanoma and acute myeloid leukemia, including patient derived xenografts, and did not discriminate bulk cancer cells from cancer cell progenitors. Together these data highlight that the mammalian metabolite DDA is a promising anticancer compound with a broad range of anticancer applications. In addition, DDA and LXR are new actors in the transcriptional control of autophagy and DDA being a "first in line" driver of lethal autophagy in cancers via the LXR.

Emerging therapies for the treatment of neovascular age-related macular degeneration and diabetic macular edema.

Diabetic macular edema (DME) and choroidal neovascularization (CNV) associated with age-related macular degeneration (AMD) are the leading causes of vision loss in the industrialized world. The mainstay of treatment for both conditions has been thermal laser photocoagulation, while there have been recent advances in the treatment of CNV using photodynamic therapy with verteporfin. While both of these treatments have prevented further vision loss in a subset of patients, vision improvement is rare. Anti-vascular endothelial growth factor (VEGF)-A therapy has revolutionized the treatment of both conditions. Pegaptanib, an anti-VEGF aptamer, prevents vision loss in CNV, although the performance is similar to that of photodynamic therapy. Ranibizumab, an antibody fragment, and bevacizumab, a full-length humanized monoclonal antibody against VEGF, have both shown promising results, with improvements in visual acuity in the treatment of both diseases. VEGF trap, a modified soluble VEGF receptor analog, binds VEGF more tightly than all other anti-VEGF therapies, and has also shown promising results in early trials. Other treatment strategies to decrease the effect of VEGF have used small interfering RNA to inhibit VEGF production and VEGF receptor production. Corticosteroids have shown efficacy in controlled trials, including anacortave acetate in the treatment and prevention of CNV, and intravitreal triamcinolone acetonide and the fluocinolone acetonide implant in the treatment of DME. Receptor tyrosine kinase inhibitors, such as vatalanib, inhibit downstream effects of VEGF, and have been effective in the treatment of CNV in early studies. Squalamine lactate inhibits plasma membrane ion channels with downstream effects on VEGF, and has shown promising results with systemic administration. Initial results are also encouraging for other growth factors, including pigment epithelium-derived factor administered via an adenoviral vector. Ruboxistaurin, which decreases protein kinase C activity, has shown positive results in the prevention of diabetic retinopathy progression, and the resolution of DME. Combination therapy has been investigated, and may prove to be quite effective in the management of both DME and AMD-associated CNV, although ongoing and future studies will be crucial to treatment optimization for each condition.

Squalamine: a polyvalent drug of the future?

The purpose of this mini-review is to summarize and highlight the different advances in our understanding of the antimicrobial and antiangiogenic activity of squalamine, a cationic steroid isolated in 1993 from the dogfish shark Squalus Acanthias. Indeed, squalamine has shown to be useful for the treatment of important diseases such as cancers (lung, ovarian, brain and others), age-related macular degeneration (AMD) and the control of body weight in man. All these results led to a question: could we consider squalamine as a polyvalent drug of the future?

Squalamine lactate for exudative age-related macular degeneration.

Squalamine lactate inhibits angiogenesis by a long-lived, intracellular mechanism of action. The drug is taken up into activated endothelial cells through caveolae, small invaginations in the cellular membrane. Subsequently, the drug binds to and "chaperones" calmodulin to an intracellular membrane compartment and blocks angiogenesis at several levels. A series of basic investigations, preclinical studies, and human clinical trials have begun to establish the proof of concept, efficacy, and safety parameters for use of squalamine lactate as a therapeutic agent for exudative age-related macular degeneration and several types of malignancies.

Naturally occurring marine steroid 24-methylenecholestane-3ß,5α,6ß,19-tetraol functions as a novel neuroprotectant.

Steroids have been shown to have multiple effects on the nervous system including neuroprotective activities, and they have the potential to be used for the treatment of neurodegenerative diseases. In this current study, we tested the hypothesis that the marine steroid 24-methylenecholestane-3ß,5α,6ß,19-tetraol (Tetrol) has a neuroprotective effect. (1) We synthesized Tetrol through a multiple step reaction starting from hyodeoxycholic acid (HDCA). (2) We then evaluated the neuroprotective effect of Tetrol with a glutamate-induced neuronal injury model in vitro. Tetrol concentration dependently increased the survival rate of cerebellar granule neurons challenged with toxic concentration of glutamate. Consistently, Tetrol significantly decreased glutamate-induced lactate dehydrogenase (LDH) release with a threshold concentration of 2.5 µM. (3) We further evaluated the neuroprotective effect of Tetrol in a middle cerebral artery occlusion (MCAO)-induced cerebral ischemia model in rat. Tetrol, at a dose of 12 mg/kg, significantly decreased MCAO-induced infarction volume by ∼50%. (4) Finally, we probed the mechanism and found that Tetrol concentration dependently attenuated N-methyl-d-aspartate (NMDA)-induced intracellular calcium ([Ca(2+)]i) increase with an IC50 of 7.8±0.62 µM, and inhibited NMDA currents in cortical neurons with an IC50 of 10.28±0.71 µM. Taken together, we have synthesized and characterized Tetrol as a novel neuroprotectant through negative modulation of NMDA receptors.

Squalamine and cisplatin block angiogenesis and growth of human ovarian cancer cells with or without HER-2 gene overexpression.

Angiogenesis is important for growth and progression of ovarian cancers. Squalamine is a natural antiangiogenic sterol, and its potential role in treatment of ovarian cancers with or without standard cisplatin chemotherapy was assessed. Since HER-2 gene overexpression is associated with cisplatin resistance in vitro and promotion of tumor angiogenesis in vivo, the response of ovarian cancer cells with or without HER-2 gene overexpression to squalamine and cisplatin was evaluated both in tumor xenograft models and in tissue culture. Ovarian cancer cells with or without HER-2 overexpression were grown as subcutaneous xenografts in nude mice. Animals were treated by intraperitoneal injection with control vehicle, cisplatin, squalamine or cisplatin combined with squalamine. At the end of the experiment, tumors were assessed for tumor growth inhibition and for changes in microvessel density and apoptosis. Additional in vitro studies evaluated effects of squalamine on tumor and endothelial cell growth and on signaling pathways in human endothelial cells. Profound growth inhibition was elicited by squalamine alone and by combined treatment with squalamine and cisplatin for both parental and HER-2-overexpressing ovarian tumor xenografts. Immunohistochemical evaluation of tumors revealed decreased microvessel density and increased apoptosis. Although HER-2-overexpressing tumors had more angiogenic and less apoptotic activity than parental cancers, growth of both tumor types was similarly suppressed by treatment with squalamine combined with cisplatin. In in vitro studies, we found that squalamine does not directly affect proliferation of ovarian cells. However, squalamine significantly blocked VEGF-induced activation of MAP kinase and cell proliferation in human vascular endothelial cells. The results suggest that squalamine is anti-angiogenic for ovarian cancer xenografts and appears to enhance cytotoxic effects of cisplatin chemotherapy independent of HER-2 tumor status.

A Phase I and pharmacokinetic study of squalamine, an aminosterol angiogenesis inhibitor.

PURPOSE: The purpose of this study was to assess the feasibility and characterize the pharmacokinetics of squalamine administered as a continuous i.v. infusion daily for 5 days every 3 weeks. EXPERIMENTAL DESIGN: Patients with advanced solid malignancies were treated with escalating doses of squalamine as a 5-day continuous i.v. infusion every 3 weeks. Doses were initially escalated in 100% increments from a starting dose of 6 mg/m(2)/day, with a single patient treated at each dose level until moderate toxicity was observed, at which time additional patients were treated. RESULTS: Thirty-three patients were treated with 73 courses of squalamine at 13 dose levels ranging from 6 to 700 mg/m(2)/day. Hepatotoxicity, characterized by brief, asymptomatic elevations in transaminases and hyperbilirubinemia, was the principal dose-limiting toxicity of squalamine. At 700 mg/m(2)/day, two of three patients developed grade 4 hyperbilirubinemia, which precluded further dose escalation. At 500 mg/m(2)/day, one of seven patients experienced dose-limiting grade 4 hyperbilirubinemia and grade 3 neurosensory changes, which resolved soon after treatment. Squalamine pharmacokinetics were dose-proportional. At 500 mg/m(2)/day, the mean (percentage coefficient of variation) clearance, half-life, and volume of distribution of squalamine were 2.67 liters/h/m(2) (85%), 9.46 h (81%), and 36.84 liters/m(2) (124%), respectively, and steady-state concentrations [20.08 micro g/ml (13%)] were well above those that inhibit angiogenesis in preclinical models. CONCLUSIONS: At the recommended Phase II dose of 500 mg/m(2)/day, squalamine is well tolerated and results in plasma concentrations at least an order of magnitude higher than those required for prominent antiangiogenic effects in preclinical studies.

A phase I/IIA trial of continuous five-day infusion of squalamine lactate (MSI-1256F) plus carboplatin and paclitaxel in patients with advanced non-small cell lung cancer.

PURPOSE: Squalamine is an antitumor agent that has been shown to have antiangiogenic activity in animal models. This Phase I/IIA study was designed to assess the safety, clinical response, and pharmacokinetics of squalamine when administered as a 5-day continuous infusion in conjunction with standard chemotherapy every 3 weeks in patients with stage IIIB (pleural effusion) or stage IV non-small cell lung cancer. EXPERIMENTAL DESIGN: Patients with chemotherapy-naive non-small cell lung cancer were treated with escalating doses of squalamine in combination with standard doses of paclitaxel and carboplatin. Paclitaxel and carboplatin were administered on day 1, followed by squalamine as a continuous infusion on days 1-5, every 21 days. RESULTS: A total of 45 patients were enrolled (18 patients in the Phase I dose escalation arm and 27 in the Phase IIA arm). The starting dose of squalamine was 100 mg/m(2)/day and escalated to 400 mg/m(2)/day; two of three patients at 400 mg/m(2)/day had dose-limiting toxicity that included grade 3/4 arthralgia, myalgia, and neutropenia. On the basis of safety and toxicity, 300 mg/m(2)/day was selected as the Phase II dose of squalamine in this combination regimen. An additional 27 patients (a total of 33) were enrolled according to the protocol treatment schema at 300 mg/m(2)/day. There was no pharmacokinetic evidence of drug interactions for the combination of squalamine, carboplatin, and paclitaxel. Forty-three patients were evaluable for response. Partial tumor responses were observed in 12 (28%) of these patients; an additional 8 evaluable patients (19%) were reported to have stable disease. For all of the patients treated, the median survival was 10.0 months; and 1-year survival was 40%. CONCLUSIONS: The combination of squalamine given continuously daily for 5 days, with paclitaxel and carboplatin given on day 1, is well tolerated. Patient survival data and the safety profile of this drug combination suggests that the use of squalamine given at its maximum tolerated dose with cytotoxic chemotherapy should be explored further as a potentially effective therapeutic strategy for patients with stage IIIB or IV non-small cell lung cancer.

Dendrogenin A: A Mammalian Metabolite of Cholesterol with Tumor Suppressor and Neurostimulating Properties.

Cholesterol-5,6-epoxide hydrolase (ChEH) in mammals is a heterooligomeric complex of two cholesterogenic enzymes that control mammalian developmental programs. Following the identification of this complex, it was hypothesized that a new metabolic pathway existed that centered on 5,6-epoxy cholesterols (5,6-EC). Conjugation products of 5,6-EC with biogenic amines known to interact with ChEH subunits were synthesized. According to their structures, these steroidal alkaloids showed the specific potency to induce cell differentiation at low doses, suggesting their possible existence as metabolites. One of these compounds, named dendrogenin A (DDA), was recently discovered in mammalian tissues. It was shown that DDA arises from the stereoselective enzymatic conjugation of 5,6α-epoxy-cholesterol with histamine by an as-yet-unidentified enzyme. DDA was detected in normal tissues from several organs but not in cancer cells and its level was decreased in breast tumors from patients, evidencing a deregulation of DDA metabolism during carcinogenesis. DDA was also able to control the growth of tumor cells implanted in mice and improve animal survival. In addition, DDA efficiently restored hearing in a preclinical model of deafness. These biological properties of DDA, as well as its decreased levels in tumors, suggest a physiological function in maintaining cell integrity and differentiation. DDA is the first steroidal alkaloid found to date in mammals. Its discovery reveals the existence of a new metabolic pathway in mammals at the crossroads of cholesterol and histamine metabolism that leads to the production of a metabolic tumor suppressor and neuroprotective agent.

Characterization of a Synthetic Steroid 24-keto-cholest-5-en-3ß, 19-diol as a Neuroprotectant.

BACKGROUND: Neuroactive steroids represent promising candidates for the treatment of neurological disorders. Our previous studies identified an endogenous steroid cholestane-3ß, 5α, 6ß-triol (Triol) as a novel neuroprotectant. AIM: We aimed to identify a potent candidate for stroke treatment through a screening of Triol analogs. METHODS: Hypoxia- and glutamate-induced neuronal injury models in vitro, middle cerebral artery occlusion (MCAO)-induced cerebral ischemia model in vivo, fluorescein diacetate (FDA) for alive and propidium iodide (PI) for dead staining, LDH assay, and calcium imaging techniques were used. RESULTS: 24-keto-cholest-5-en-3ß, 19-diol (Diol) showed the most potent neuroprotective effect among the screened structurally related compounds. FDA and PI staining showed that Diol concentration dependently increased the survival rate of cerebellar granule neurons (CGNs) challenged with glutamate or hypoxia, with an effective threshold concentration of 2.5 µM. Consistently, the quantitative LDH release assay showed the same concentration-dependent protection in both models. Diol, at 10 µM, potently decreased glutamate- and hypoxia-induced LDH release from 51.6 to 18.2% and 62.1 to 21.7%, respectively, which values are close to the normal LDH release (~16-18%). Moreover, we found Diol effectively decreased MCAO-induced infarction volume in mice from ~23% to 7%, at a dose of 6 mg/kg. We further explored the underlying mechanism and found that Diol attenuated NMDA-induced intracellular calcium ([Ca(2+) ]i ) increase in cortical neurons, suggesting a negative modulatory effect on NMDA receptor. CONCLUSION: Taken together, we identified Diol as a potent neuroprotectant. It may represent a novel and promising neuroprotectant for stroke intervention.

Squalamine improves retinal neovascularization.

PURPOSE: Modalities for inhibiting neovascularization may be one avenue to the development of effective therapies for retinopathy. The effect of squalamine, an antiangiogenic amino sterol, on oxygen-induced retinopathy (OIR) was assessed in a mouse model. METHODS: OIR was induced in C57BL6 mice by a 5-day exposure to 75% oxygen from postnatal day (P)7 through P12. Squalamine (25 mg/kg, subcutaneous)treated animals received either daily doses for five days from P12 to P16 or one dose just after removal from oxygen on P12. Each set of animals was killed at P17 to P21. Retinopathy was assessed with a retinopathy scoring system evaluation of retinal wholemounts and by quantification of neovascular nuclei on retinal sections. RESULTS: Animals receiving 5 days of squalamine after a 5-day exposure to oxygen had total retinopathy scores (expressed as median score with 25th and 75th quartiles in parentheses) of 4(3, 5) versus oxygen-only-reared animals with scores of 8(7, 9; P < 0.001). Animals reared in room air and animals exposed to squalamine only had similar retinopathy scores: 1(1, 2) and 1(0, 2). Oxygen-reared animals receiving single-dose squalamine also showed improvement, with a median retinopathy score of 4(4, 6.75) versus oxygen-only-reared animals with median retinopathy score of 9(7, 10; P < 0.001). There was a decreased number of neovascular nuclei extending beyond the inner limiting membrane on retinal sections in animals treated with 5 days (P < 0.01) and 1 day (P < 0.001) of squalamine. CONCLUSIONS: Squalamine significantly improved retinopathy and may be a novel agent for effective treatment of ocular neovascularization.

Potential of the aminosterol, squalamine in combination therapy in the rat 13,762 mammary carcinoma and the murine Lewis lung carcinoma.

Squalamine, a naturally-occurring aminosterol, has demonstrated antiangiogenic activity in several experimental models. Extended treatment with other antiangiogenic agents has been shown to increase tumor oxygenation. Tumor oxygenation was measured using an Eppendorf pO2 histograph polarographic pO2 electrode system in the rat 13,762 mammary carcinoma after treatment of the tumor-bearing animals with squalamine (40 mglkg) on days 4 through 18 post tumor implantation. Under air breathing conditions, the hypoxic fraction (percent of pO2 readings < 5 mmHg) was 53% in controls and was decreased to 38% in the squalamine treated animals. While squalamine administration alone produced only a modest effect on the growth of the 13,762 tumor, there were increases in tumor growth delay of 1.9- to 2.5-fold when squalamine was administered along with cyclophosphamide, cisplatin and paclitaxel compared with the tumor growth delays observed with the chemotherapeutic agents alone. To determine the efficacy of squalamine alone and along with cytotoxic therapies against a model of primary and systemic disease, squalamine was administered to animals bearing the Lewis lung carcinoma by daily subcutaneous injection or by continuous infusion on days 4 through 18 post tumor implantation. Squalamine as a single agent had only a modest effect on the growth of the primary Lewis lung tumor but increased the tumor growth delays produced by cyclophosphamide, cisplatin, paclitaxel and 5-fluorouracil by 2.4- to 3.8-fold compared with the anticancer drugs alone. Squalamine administration alone substantially decreased the number of lung metastases found in animals bearing the Lewis lung carcinoma and further decreased the number of lung metastases when administered along with the chemotherapeutic agents.

[Protective effect of huyin decoction on acute hepatic injury induced by CCl4 in mice].

OBJECTIVE: To observe the protective effect of Huyin decoction on acute hepatic injury induced by CCl4 in mice. METHODS: The model of acute hepatic injury induced by CCl4 was used. The levels of ALT and AST in serum were detected. And histopathology of liver was observed. RESULTS: Huyin decoction could decrease ALT and AST in serum and hepatic histopathological injury of the acute hepatic injury mice. CONCLUSION: Huyin decoction possessed protective effect on acute hepatic injury in mice.

Enhanced expression of proapoptotic and autophagic proteins involved in the cell death of glioblastoma induced by synthetic glycans.

OBJECT: Glioblastoma is the most aggressive malignant brain tumor, and overall patient survival has not been prolonged even by conventional therapies. Previously, the authors found that chemically synthesized glycans could be anticancer agents against growth of a series of cancer cells. In this study, the authors examined the effects of glycans on the growth of glioblastoma cells both in vitro and in vivo. METHODS: The authors investigated not only the occurrence of changes in the cell signaling molecules and expression levels of various proteins related to cell death, but also a mouse model involving the injection of glioblastoma cells following the administration of synthetic glycans. RESULTS: Synthetic glycans inhibited the growth of glioblastoma cells, induced the apoptosis of the cells with cleaved poly (adenosine diphosphate-ribose) polymerase (PARP) expression and DNA fragmentation, and also caused autophagy, as shown by the detection of autophagosome proteins and monodansylcadaverine staining. Furthermore, tumor growth in the in vivo mouse model was significantly inhibited. A dramatic induction of programmed cell death was found in glioblastoma cells after treatment with synthetic glycans. CONCLUSIONS: These results suggest that synthetic glycans could be a promising novel anticancer agent for performing chemotherapy against glioblastoma.

Dendrogenin A arises from cholesterol and histamine metabolism and shows cell differentiation and anti-tumour properties.

We previously synthesized dendrogenin A and hypothesized that it could be a natural metabolite occurring in mammals. Here we explore this hypothesis and report the discovery of dendrogenin A in mammalian tissues and normal cells as an enzymatic product of the conjugation of 5,6α-epoxy-cholesterol and histamine. Dendrogenin A was not detected in cancer cell lines and was fivefold lower in human breast tumours compared with normal tissues, suggesting a deregulation of dendrogenin A metabolism during carcinogenesis. We established that dendrogenin A is a selective inhibitor of cholesterol epoxide hydrolase and it triggered tumour re-differentiation and growth control in mice and improved animal survival. The properties of dendrogenin A and its decreased level in tumours suggest a physiological function in maintaining cell integrity and differentiation. The discovery of dendrogenin A reveals a new metabolic pathway at the crossroads of cholesterol and histamine metabolism and the existence of steroidal alkaloids in mammals.

Synthesis of new alkylaminooxysterols with potent cell differentiating activities: identification of leads for the treatment of cancer and neurodegenerative diseases.

We describe here the syntheses and the biological properties of new alkylaminooxysterols. Compounds were synthesized through the trans-diaxial aminolysis of 5,6-alpha-epoxysterols with various natural amines including histamine, putrescine, spermidine, or spermine. The regioselective synthesis of these 16 new 5alpha-hydroxyl-6beta-aminoalkylsterols is presented. Compounds were first screened for dendrite outgrowth and cytotoxicity in vitro, and two leads were selected and further characterized. 5alpha-Hydroxy-6beta-[2-(1H-imidazol-4-yl)ethylamino]cholestan-3beta-ol, called dendrogenin A, induced growth control, differentiation, and the death of tumor cell lines representative of various cancers including metastatic melanoma and breast cancer. 5alpha-Hydroxy-6beta-[3-(4-aminobutylamino)propylamino]cholest-7-en-3beta-ol, called dendrogenin B, induced neurite outgrowth on various cell lines, neuronal differentiation in pluripotent cells, and survival of normal neurones at nanomolar concentrations. In summary, we report that two new alkylaminooxysterols, dendrogenin A and dendrogenin B, are the first members of a class of compounds that induce cell differentiation at nanomolar concentrations and represent promising new leads for the treatment of cancer or neurodegenerative diseases.

Promising new treatments for neovascular age-related macular degeneration.

Angiogenesis, the growth of new blood vessels from existing blood vessels, is responsible for vision loss in a variety of ophthalmic diseases. In neovascular age-related macular degeneration (AMD), the leading cause for legal blindness in many industrialised countries, abnormal blood vessels grow in the macula and cause blindness. There are a number of factors important in the angiogenic cascade but VEGF-A has been implicated in recent years as the major factor responsible for neovascular and exudative diseases of the eye. Numerous antiangiogenic drugs are in development but anti-VEGF drugs have shown great promise in treating neovascular AMD and other ocular diseases, and many of these drugs have been adopted from oncology where antiangiogenic therapy is gaining wide acceptance. For the first time in neovascular AMD, anti-VEGF drugs have brought the hope of vision improvement to a significant proportion of patients. This review provides an overview on angiogenic mechanisms, potential antiangiogenic treatment strategies and different antiangiogenic drugs with special focus on neovascular AMD.

Adjunctive therapy for men with high risk localized and locally advanced prostate cancer: targeting disseminated tumor cells.

PURPOSE: Our research into the pathophysiology of micrometastatic dissemination and cancer recurrence has resulted in the initiation of a clinical trial for men with clinically localized and locally advanced disease. MATERIALS AND METHODS: We describe the development of this trial, which exploits anti-angiogenesis therapy, and delineate how our understanding of prostate cancer metastasis influenced its design. RESULTS: Prostate cancer is a heterogeneous disease. Although many men can be cured with local therapy, a large majority with clinically localized disease will experience a relapse usually at a distant site. This result is most likely due to micrometastatic dissemination early in the disease process. Therefore, successful contemporary treatment of many men with prostate cancer should include a combination of local and systemic therapies. Fortunately, cellular, molecular and genetic features that may predict which men are most in need of this therapeutic approach are being identified and characterized. This insight not only supports the rationale for a combination therapeutic approach to prostate cancer management, but will help identify the pathways and agents that provide the most promising targets for intervention. CONCLUSIONS: Despite advances in prevention and early detection, refinements in surgical technique, and improvements in radiation and systemic therapies, the ability to cure all men with prostate cancer remains unattainable. The continuing challenge is the successful eradication of recurrent and metastatic disease.