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Judah Folkman

Publications and source records attributed to Judah Folkman.

At least 37 records · Page 2Linked to original sources
PubMed2005

A 27-amino-acid synthetic peptide corresponding to the NH2-terminal zinc-binding domain of endostatin is responsible for its antitumor activity.

The first recombinant endostatin that elicited strong antitumor activity was expressed in Escherichia coli and administered as a suspension. Under these conditions, the protein retained its full antiangiogenic activity. Lack of requirement for a folded structure prompted us to investigate antitumor properties of synthetic peptides corresponding to different regions of endostatin. Here, we show that the entire antitumor, antimigration, and antipermeability activities of endostatin are mimicked by a 27-amino-acid peptide corresponding to the NH2-terminal domain of endostatin. This peptide contains three histidines that are responsible for zinc binding. Mutations of the zinc-binding histidines abolished its antitumor and antimigration activities, but not antipermeability properties.

Adenocarcinoma↗
PubMed2005

Differential effects of vascular endothelial growth factor receptor-2 inhibitor ZD6474 on circulating endothelial progenitors and mature circulating endothelial cells: implications for use as a surrogate marker of antiangiogenic activity.

PURPOSE: Circulating endothelial cells (CEC) comprise at least two distinct populations: bone marrow-derived circulating endothelial progenitors (CEP) and mature CECs derived from existing vasculature. We hypothesized that antiangiogenic agents may have differential effects on CEPs and mature CECs and that these changes may serve as a marker of biological activity. EXPERIMENTAL DESIGN: The effect of angiogenesis inhibitors on CECs was evaluated by flow cytometry after vascular endothelial growth factor (VEGF)-induced mobilization and in mice bearing Lewis lung carcinoma (LLC). Tumor angiogenesis was evaluated in parallel by immunohistochemistry. RESULTS: In nontumor-bearing mice, VEGF administration increased both mature CECs and CEPs. This increase was inhibited by the VEGF receptor 2 inhibitor ZD6474 as well as the VEGF inhibitor-soluble Flt-1. ZD6474 had no significant effect on CECs in the absence of exogenous VEGF stimulation. In contrast, LLC-bearing mice had an increase in mature CECs but not CEPs after 3 days of treatment with ZD6474. The increase in mature CECs was dose-dependent, accompanied by a decrease in tumor microvessel density, and preceded reduction in tumor volume. Treatment of LLC-bearing mice with the vascular targeting agent ZD6126 also increased mature CECs. CONCLUSIONS: VEGF inhibitors can have differential effects on mature CECs and CEPs, and agents inhibiting tumor angiogenesis may cause a concomitant increase in mature CECs. This increase occurs in tumor-bearing but not in nontumor-bearing mice, suggesting that tumor endothelium is a potential source of mature CECs. Therefore, assessing both mature CECs and CEPs may provide insights into the mechanism of antiangiogenic agents and serve as an early surrogate marker of biological activity.

Animals↗
PubMed2005

CDK2 translational down-regulation during endothelial senescence.

Here we report for the first time that loss of CDK2 activity, by translational inhibition and through CDK2 inhibition by p21(Cip1/Waf1), may be responsible for endothelial senescence. We show that expression of dominant-negative p53 extends human umbilical vein endothelial cell (HUVEC) lifespan past senescence. HUVEC expressing telomerase can completely bypass senescence and become immortal (i-HUVEC). Surprisingly, early passage i-HUVEC, like senescent HUVEC, express high levels of the CDK inhibitors p16(INK4a) and p21(Cip1/Waf1). Expression of p16(INK4a) can persist for over 280 population doublings, while p21(Cip1/Waf1) expression was eventually lost in five of six i-HUVEC lines. Senescent HUVEC contain undetectable CDK2 activity, which results from a dramatic reduction of CDK2 protein levels and inhibition of remaining CDK2 by p21(Cip1/Waf1). The decreased CDK2 levels in senescent HUVEC are not due to decreased transcription or protein stability; rather, CDK2 translation declines during senescence. Bypass of endothelial senescence by telomerase entails the restoration of CDK2 translation and activity. These results suggest that p16(INK4a) does not play a role in endothelial senescence. Rather, CDK2 translational down-regulation may be a key regulatory event in replicative senescence of endothelial cells. Understanding the mechanisms regulating endothelial senescence will be critical in determining the role of endothelial senescence in tumor growth.

Blotting, Western↗
PubMed2005

Omega-3 fatty acid supplementation prevents hepatic steatosis in a murine model of nonalcoholic fatty liver disease.

Prolonged use of total parenteral nutrition can lead to nonalcoholic fatty liver disease, ranging from hepatic steatosis to cirrhosis and liver failure. It has been demonstrated that omega-3 fatty acids are negative regulators of hepatic lipogenesis and that they can also modulate the inflammatory response in mice. Furthermore, they may attenuate hepatic steatosis even in leptin-deficient ob/ob mice. We hypothesized that omega-3 fatty acid supplementation may protect the liver against hepatic steatosis in a murine model of parenteral nutrition in which all animals develop steatosis and liver enzyme disturbances. For testing this hypothesis, groups of mice received a fat-free, high-carbohydrate liquid diet ad libitum for 19 d with enteral or i.v. supplementation of an omega-3 fatty acid emulsion or a standard i.v. lipid emulsion. Control mice received food alone or the fat-free, high-carbohydrate diet without lipid supplementation. Mice that received the fat-free, high-carbohydrate diet only or supplemented with a standard i.v. lipid emulsion developed severe liver damage as determined by histology and magnetic resonance spectroscopy as well as elevation of serum liver function tests. Animals that received an i.v. omega-3 fatty acid emulsion, however, showed only mild deposits of fat in the liver, whereas enteral omega-3 fatty acids prevented hepatic pathology and led to normalization of liver function tests. In conclusion, whereas standard i.v. lipid emulsions fail to improve dietary-induced steatotic injury to the liver, i.v. supplementation of omega-3 fatty acids partially and enteral supplementation completely protects the liver against such injury.

Animals↗
PubMed2005

Inhibition of vessel permeability by TNP-470 and its polymer conjugate, caplostatin.

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.

Angiogenesis Inhibitors↗
PubMed2005

Nonsteroidal antiinflammatory drugs differentially suppress endometriosis in a murine model.

OBJECTIVE: To determine whether nonsteroidal antiinflammatory drugs (NSAIDs) affect the establishment and progression of endometriotic lesions in a murine model. DESIGN: Pharmacologic intervention in a surgically induced murine model of abdominal/peritoneal endometriosis. SETTING: Animal research facility. PATIENT(S): Eight-week-old, female C57BL/6 mice. INTERVENTION(S): After implantation of autologous endometrium, mice were randomized into groups and treated with one of several NSAIDs or the vehicle-matched control for 4 weeks. MAIN OUTCOME MEASURE(S): Establishment, growth, and total burden of endometriotic lesions. RESULT(S): The NSAIDs differentially inhibited lesion establishment and growth, resulting in significantly reduced disease burden. Compared with controls (5.7 +/- 2.3 mm(2)), lesion burden was reduced by celecoxib (1.3 +/- 1.2 mm(2)), indomethacin (1.4 +/- 1.4 mm(2)), naproxen (2.7 +/- 1.2 mm(2)), sulindac (3.1 +/- 1.5 mm(2)), rofecoxib (3.4 +/- 3.0 mm(2)), and ibuprofen (4.1 +/- 1.4 mm(2)). In contrast, aspirin (5.9 +/- 1.2 mm(2)) had no statistically significant effect. Uninterrupted estrus cycling was confirmed by vaginal exams and smears in celecoxib-treated mice. CONCLUSION(S): Chronic administration of certain NSAIDs limits the progression of endometriosis in this murine model. The data suggest that NSAID selection in the treatment of endometriosis should be extended beyond pain management to maximize the inhibitory effect on disease burden.

Animals↗
PubMed2005

Endostatin inhibits the growth of endometriotic lesions but does not affect fertility.

OBJECTIVE: To determine whether endometriosis can be treated with the angiogenesis inhibitor endostatin and the effect of this treatment on fertility and reproduction. DESIGN: Pharmacologic intervention in a surgically induced model of endometriosis and in female mice undergoing mating. SETTING: Animal research facility. ANIMAL(S): Eight-week-old, female C57BL/6 and SCID mice. INTERVENTION(S): After implantation of autologous endometrium, mice received endostatin or the vehicle-matched control for 4 weeks. For the reproductive function study, mice receiving endostatin or vehicle were mated and reproductive functions were observed. MAIN OUTCOME MEASURE(S): Growth of endometriotic lesions after 4 weeks of treatment; estrous cycling, corpus luteum formation, serum hormone levels, and mating time as fertility measures; and pregnancy rates, length of pregnancy, fetal vitality, number, and outcome of litter as reproductive measures. RESULT(S): Endostatin suppressed the growth of endometriotic lesions by 47% compared with controls. Estrous cycling and corpus luteum formation were normal in both groups. Female mice receiving endostatin were as fertile as mice receiving vehicle, had normal pregnancies, and delivered the same number of pups. The offspring were healthy without teratogenic stigmata and reproduced normally themselves. CONCLUSION(S): Antiangiogenic therapy with endostatin may present a promising novel, nontoxic therapeutic option for patients with endometriosis.

Angiogenesis Inhibitors↗
PubMed2005

The route of lipid administration affects parenteral nutrition-induced hepatic steatosis in a mouse model.

BACKGROUND: The etiology of parenteral nutrition (PN)-associated hepatic injury remains unresolved. Recent studies have suggested that the intravenous (IV) lipid emulsion administered with PN may contribute to PN-associated hepatic injury. We therefore examined whether the route of lipid administration would affect the development of PN-associated liver injury in a previously established animal model of PN-induced hepatic steatosis. METHODS: Mice were fed ad libitum PN solution as their only nutritional source for 19 days with lipid supplementation by either the enteral or the IV route. Control mice received chow alone, and a final group received enteral PN solution without lipid supplementation. RESULTS: All mice gained equivalent weight during the study. Mice receiving PN alone or PN with IV lipid developed severe histologic liver damage that was not seen in control mice or in mice receiving PN with enteral lipid. Liver fat content as measured by magnetic resonance spectroscopy was significantly lower in the control and enteral lipid groups when compared with mice receiving PN alone or with IV lipid. Mice receiving enteral lipid had significantly lower levels of serum aspartate aminotransferase and alanine aminotransferase compared with animals receiving PN alone. CONCLUSIONS: These data provide preliminary evidence that lipid administered through the enteral route protects against PN-associated hepatic injury in an animal model.

Animals↗
PubMed2005

A feasibility trial of antiangiogenic (metronomic) chemotherapy in pediatric patients with recurrent or progressive cancer.

Standard chemotherapeutic drugs, when modified by the frequency and dose of administration, can target angiogenesis. This approach is referred to as antiangiogenic chemotherapy, low-dose chemotherapy, or metronomic chemotherapy. This study evaluated the feasibility of 6 months of metronomic chemotherapy, its toxicity and tolerability, surrogate markers of activity, and preliminary evidence of activity in children with recurrent or progressive cancer. Twenty consecutive children were enrolled and received continuous oral thalidomide and celecoxib with alternating oral etoposide and cyclophosphamide every 21 days for a planned duration of 6 months using antiangiogenic doses of all four drugs. Surrogate markers including bFGF, VEGF, endostatin, and thrombospondin were also evaluated. Therapy was well tolerated in this heavily pretreated population. Toxicities (predominantly reversible bone marrow suppression) responded to dose modifications. Sixty percent of the patients received less than the prescribed 6 months of therapy due to toxicity (one case of deep vein thrombosis), personal choice (1 patient), or disease progression (10 patients). Forty percent of the patients completed the 6 months of therapy, resulting in prolonged or persistent disease-free status. One quarter of all patients continue to be progression free more than 123 weeks from starting therapy. Sixteen percent of patients showed a radiographic partial response. Only elevated thrombospondin-1 levels appeared to correlate with prolonged response. This oral antiangiogenic chemotherapy regimen was well tolerated in this heavily pretreated pediatric population, which showed prolonged or persistent disease-free status, supporting the continued study of antiangiogenic/metronomic chemotherapy in human clinical trials.

Administration, Oral↗
PubMed2005

Blue rubber bleb nevus syndrome: surgical eradication of gastrointestinal bleeding.

OBJECTIVE: We report the largest clinical experience to date of surgically treated patients with blue rubber bleb nevus syndrome (BRBNS). SUMMARY BACKGROUND DATA: BRBNS is a rare congenital disorder presenting with multifocal venous malformations of the skin, soft tissues, and gastrointestinal (GI) tract. Patients with BRBNS develop anemia from chronic GI bleeding, and require lifelong treatment with iron and blood transfusions. An aggressive surgical approach to treat the GI venous malformations of BRBNS has been considered unlikely to be successful because of the large number of lesions, their position throughout the GI tract, and the likelihood of recurrence. Based on our belief that eradicated lesions would not recur, we undertook the removal of all GI tract lesions in an effort to eliminate bleeding. METHODS: Ten patients with BRBNS were treated from 1993 to 2002. Lesions were identified using complete GI endoscopy. The multiple venous malformations were removed by a combination of wedge resection, polypectomy, suture-ligation, segmental bowel resection, and band ligation. RESULTS: Patient ages ranged from 2 to 36 years, and patients received an average of 53 prior blood transfusions. A mean of 137 focal GI venous malformations per patient were resected at operation (range 4-557), with a mean operative duration of 14 hours (range 7-23 hours). Only 1 patient who had a less extensive procedure developed recurrent GI bleeding. The mean follow-up period was 5.0 years (range 2.9-10.3 years). CONCLUSIONS: We believe that an aggressive excisional approach is indicated for the venous anomalies that cause GI bleeding in BRBNS.

Adolescent↗
PubMed2005

Prevention of intra-abdominal adhesions using the antiangiogenic COX-2 inhibitor celecoxib.

OBJECTIVE: To determine the effects of COX-2 specific inhibitors on postoperative adhesion formation. SUMMARY AND BACKGROUND DATA: Intra-abdominal adhesions are the major cause of intestinal obstruction and secondary infertility after surgical procedures. Because adhesion synthesis requires angiogenesis, and cyclooxygenase-2 enzyme (COX-2) inhibitors have antiendothelial activity, we tested COX-2 inhibitors in a murine model of intra-abdominal adhesion formation. METHODS: A silicone patch was secured to the lateral abdominal wall of groups of C57BL/6 mice, followed by cecal abrasion to promote adhesion formation. Beginning on the day of surgery, mice were treated with the selective COX-2 agents, celecoxib or rofecoxib, and the nonspecific COX inhibitors, aspirin, naproxen, ibuprofen, or indomethacin. Animals were treated for 10 days and killed. A second group (celecoxib, rofecoxib, aspirin) was treated for 10 days and observed for an additional 25 days. After treatment, intra-abdominal adhesions were scored using a standard method. The patch was subjected to immunohistochemistry with the endothelial-specific marker, CD31. RESULTS: Animals treated with selective and nonselective COX-2 inhibitors, except aspirin, had significantly fewer adhesions than control animals. Celecoxib produced a maximal reduction in adhesion formation compared with rofecoxib and the nonselective COX-2 inhibitors at 10 days. After 25 days, celecoxib and rofecoxib, but not aspirin, had fewer adhesions than control mice. Adhesions from mice treated with celecoxib had reduced microvessel density compared with rofecoxib, the nonselective COX inhibitors, and control animals. CONCLUSIONS: Selective COX-2 inhibitors, in particular celecoxib, provide durable inhibition of intra-abdominal adhesions through an antiangiogenic mechanism.

Animals↗
PubMed2005

Role of vascular endothelial growth factor-A in recurrent respiratory papillomatosis.

Vascular endothelial growth factor-A (VEGF-A) is known to play an important role in the angiogenic response essential for tumor growth in a variety of human and experimental tumors. This study was designed to investigate whether VEGF-A may play a role in the pathogenesis of recurrent respiratory papillomatosis (RRP). A retrospective study with institutional review board approval was performed at a tertiary care medical center on 12 patients with a history of laryngeal RRP. Their ages at the time of initial diagnosis ranged from 19 to 96 months (mean, 56 months). All patients had involvement of right and left true vocal cords. All patients required multiple endoscopic procedures (range, 4 to 66; mean, 12). Normal pediatric larynx samples from 5 autopsy patients were used as controls. Formalin-fixed, paraffin-embedded sections of laryngeal squamous papillomas from the 12 patients with a diagnosis of RRP and the 5 control patients were examined by in situ hybridization for the presence of messenger RNA (mRNA) for VEGF-A and vascular endothelial growth factor receptor 1 (VEGFR-1) and vascular endothelial growth factor receptor 2 (VEGFR-2). The biopsy specimens were from the true vocal cord (N = 10) or subglottis (N = 2) in the patients with RRP and consisted of large sections of larynx including the true vocal cord in the control patients (N = 5). Strong expression of VEGF-A mRNA was noted in the squamous epithelium of papillomas of all 12 patients. Strong expression of VEGFR-1 and VEGFR-2 was noted in the endothelial cells of the underlying vessels in all 12 patients. Neither strong labeling of VEGF-A mRNA nor labeling of its receptors wasnoted in the control patients. We conclude that the angiogenic growth factor VEGF-A is strongly expressed in the epithelium of squamous papillomas in RRP. Also, VEGFR-1 and VEGFR-2 mRNAs are strongly expressed by underlying vascular endothelial cells, suggesting an important role in the pathogenesis of RRP.

Biopsy↗
PubMed2005

Increased expression of urinary matrix metalloproteinases parallels the extent and activity of vascular anomalies.

OBJECTIVE: Matrix metalloproteinases (MMPs) and the angiogenic proteins basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) have been implicated in mechanisms of human cancer and metastasis. Assays were conducted on the urine of patients with vascular anomalies (tumors and malformations), relatively common and occasionally life-threatening disorders for which few therapies exist. We sought to determine whether these angiogenesis modulators are present in the urine and whether their expression is associated with the extent and clinical course of the vascular lesion. METHODS: A total of 217 patients with vascular anomalies and 74 age-matched control subjects participated. Urinary MMP expression was determined by substrate gel electrophoresis. Urinary bFGF and VEGF levels were measured by enzyme-linked immunosorbent assay. Each patient was assigned to 1 of 2 categories (tumor or malformation) and 1 of 9 specific groups. Extent of the vascular lesion and activity were scored by a blinded clinician. RESULTS: Urinary high molecular weight (hMW) MMPs and bFGF were significantly increased in patients with vascular tumors (53%) and vascular malformations (41%), compared with control subjects (22%). These percentages increased as a function of extent of the lesion and disease activity. hMW MMPs were increased in 4 groups: infantile hemangioma, other vascular neoplasms, lymphatic malformation and capillary-lymphaticovenous malformations, and extensive and unremitting capillary malformation and arteriovenous malformation. No significant differences among the groups were detected for low molecular weight MMPs or VEGF. CONCLUSIONS: Expression patterns of hMW MMPs and bFGF in the urine of patients with tumors and malformations are consistent with their different clinical behavior. These data represent the first evidence that MMPs are elevated in the urine of children with vascular anomalies. These data also suggest that the increased expression of urinary MMPs parallels the extent and activity of vascular anomalies in children. In addition to tumors, vascular malformations are angiogenesis dependent, suggesting that progression of a vascular malformation might be suppressed by angiogenic inhibitors, which would target bFGF and MMPs.

Adolescent↗
PubMed2004

Urinary matrix metalloproteinases and their endogenous inhibitors predict hepatic regeneration after murine partial hepatectomy.

BACKGROUND: Matrix metalloproteinases (MMPs) play a key role in extracellular matrix remodeling events associated with hepatic regeneration after partial hepatectomy. We therefore hypothesized that urinary MMPs and their endogenous tissue inhibitors of matrix metalloproteinases (TIMPs) might also provide important information regarding initiation and progression of liver regeneration. METHODS: Groups of 20 mice underwent sham operations, two-thirds hepatectomy, or treatment with the angiogenesis inhibitor, AGM-1470,O-chloroacetyl-carbamoyl-fumagillol (TNP-470), after two-thirds hepatectomy to prevent hepatic regeneration. Urine was collected preoperatively and for 24 days after surgery and tested for MMP-2, MMP-9, TIMP-1, and TIMP-2 using substrate gel electrophoresis (zymography) and Western blot analysis. RESULTS: During hepatic regeneration, MMP-9 was detected in the urine at significantly lower levels on postoperative day 8 when the liver returned to its preoperative mass. In contrast, urine from mice whose livers were inhibited from regenerating (TNP-treated groups) contained increased levels of the gelatinases MMP-2 and MMP-9. The MMP inhibitors, TIMP-1 and TIMP-2, were significantly reduced in the urine of mice with normally regenerating livers but were increased in the urine of mice treated with TNP-470 on day 8. CONCLUSIONS: We demonstrate that (1) urinary MMPs and their cognate inhibitors, the TIMPs, can be detected in the urine of mice undergoing partial hepatectomy, (2) the presence of these remodeling proteins in the urine may predict the progressive return of the partially resected liver to its preoperative mass, and (3) analysis of urinary MMPs and TIMPs may someday provide a noninvasive means of monitoring the status of patients undergoing hepatic resection and transplantation.

Angiogenesis Inhibitors↗
PubMed2004

Phase II study of the antiangiogenic agent SU5416 in patients with advanced soft tissue sarcomas.

PURPOSE: SU5416 (semaxanib) is a small molecule inhibitor of the vascular endothelial growth factor (VEGF) receptor-2 and KIT receptor tyrosine kinases. This Phase II study was conducted to investigate the safety and efficacy of SU5416 for patients with soft tissue sarcomas. EXPERIMENTAL DESIGN: Thirteen patients with locally advanced or metastatic soft tissue sarcomas were treated with SU5416 via intravenous infusion at a dose of 145 mg/m(2) twice weekly. In selected cases tumor biopsies were taken before and after 2 months of treatment. RESULTS: The median progression-free survival was 1.8 months. Median overall survival was 22.8 months. No objective tumor responses were observed. There was evidence of shorter survival among patients with high baseline urine VEGF levels (P = 0.04). No grade 4 toxicities were observed. The most common grade 3 toxicities were headache and thrombosis. Other less serious toxicities included fatigue, nausea, and abdominal pain. The median systolic blood pressure increased from 118 mmHg at baseline to 133 after 1 month of treatment (P = 0.01). Post-treatment tumor biopsies showed no significant decreases in VEGF receptor phosphorylation compared with baseline in 3 evaluable patients. One patient with gastrointestinal stromal tumor who had rapid progression during SU5416 treatment was subsequently treated with another KIT inhibitor, imatinib mesylate, and had a partial response lasting >36 months. CONCLUSIONS: SU5416 was relatively well tolerated but did not demonstrate significant antitumor activity against advanced soft tissue sarcoma. Correlative studies suggest that VEGF receptor or KIT inhibition was incomplete in at least some cases, providing a possible explanation for the observed lack of activity.

Adult↗
PubMed2004

Dose-dependent response of FGF-2 for lymphangiogenesis.

Spatio-temporal studies on the growth of capillary blood vessels and capillary lymphatic vessels in tissue remodeling have suggested that lymphangiogenesis is angiogenesis-dependent. We revisited this concept by using fibroblast growth factor 2 (FGF-2) (80 ng) to stimulate the growth of both vessel types in the mouse cornea. When we lowered the dose of FGF-2 in the cornea 6.4-fold (12.5 ng), the primary response was lymphangiogenic. Further investigation revealed that vascular endothelial growth factor-C and -D are required for this apparent lymphangiogenic property of FGF-2, and when the small amount of accompanying angiogenesis was completely suppressed, lymphangiogenesis remained unaffected. Our findings demonstrate that there is a dose-dependent response of FGF-2 for lymphangiogenesis, and lymphangiogenesis can occur in the absence of a preexisting or developing vascular bed, i.e., in the absence of angiogenesis, in the mouse cornea.

Animals↗