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PubMed1994

Possible involvement of VEGF-FLT tyrosine kinase receptor system in normal and tumor angiogenesis.

A novel receptor-type tyrosine kinase gene flt (fms-like tyrosine kinase, flt-1) was isolated from human placenta cDNA library. Flt-1 receptor carries a ligand binding domain which contains seven immunoglobulin-like stretches. Further, Flt-1 tyrosine kinase domain is separated by an approximately 70 amino acid-insert region similar to the cases of Fms/Kit/PDGF-R (fms family). However, unlike the fms family members, Flt-1 insert region does not contain "Tyr-X-X-Met" motif, which is known to be important for signal transduction and for the binding of P13 kinase to the receptor. Thus, a unique structure of Flt-1 suggests that a signal transduction pathway from Flt receptor is different from that in the fms family. The expression of flt-1 gene is detectable in a variety of normal tissues, and cell fractionation studies indicate that the flt-1 mRNA is highly expressed in endothelial cell-enriched fraction. VEGF, which has recently been reported as a ligand for Flt-1 receptor, dramatically stimulated growth of endothelial cells in culture. Many human tumors were found to express VEGF mRNA but not Flt-1 message, suggesting a paracrine mechanism for tumor angiogenesis. Interestingly, VEGF could not stimulate proliferation of Flt-1-overexpressing NIH3T3 fibroblast cells. These results suggest that Flt-1 is an endothel-specific growth factor receptor and that the signal transducing pathway through Flt-1 receptor is inactive in the fibroblast background.

3T3 Cells↗
PubMed1997

Angiostatin: an endogenous inhibitor of angiogenesis and of tumor growth.

Angiostatin, an internal fragment of plasminogen, is a potent inhibitor of angiogenesis, which selectively inhibits endothelial cell proliferation. When given systemically, angiostatin potently inhibits tumor growth and can maintain metastatic and primary tumors in a dormant state defined by a balance of proliferation and apoptosis of the tumor cells. We identified angiostatin while studying the phenomenon of inhibition of tumor growth by tumor mass and have elucidated one mechanism for this phenomenon. In our animal model, a primary tumor almost completely suppresses the growth of its remote metastases. However, after tumor removal, the previously dormant metastases neovascularize and grow. When the primary tumor is present, metastatic growth is suppressed by a circulating angiogenesis inhibitor. Serum and urine from tumor-bearing mice, but not from controls, specifically inhibit endothelial cell proliferation. The activity copurifies with a 38 kD plasminogen fragment which we have sequenced and named angiostatin. Human angiostatin, obtained from a limited proteolytic digest of human plasminogen, has similar activities. Systemic administration of angiostatin, but not intact plasminogen, potently blocks neovascularization and growth of metastases and primary tumors. We here show that the inhibition of metastases by a primary mouse tumor is mediated, at least in part, by the angiogenesis inhibitor angiostatin.

Angiostatins↗
PubMed1996

The chick embryo chorioallantoic membrane as a model for in vivo research on angiogenesis.

The chick embryo chorioallantoic membrane (CAM) is an extraembryonic membrane that is commonly used in vivo to study both new vessel formation and its inhibition in response to tissues, cells, or soluble factors. Quantitative or semiquantitative methods may be used to evaluate the amount of angiogenesis and anti-angiogenesis. Thanks to the CAM system, angiogenesis could be investigated in association with normal, inflammatory and tumor tissues, and soluble factors inducing angiogenic or anti-angiogenic effects could be identified. Rabbit cornea provides an alternative in vivo system, but CAM appears to be easier to handle and less expensive. Moreover, CAM can be used with very few limitations.

Allantois↗
PubMedDate not supplied

[Angiogenesis].

Angiogenesis, the budding of new vessels from the preexistant capillaries and postcapillary venules, is an important biological phenomenon during reproduction, embryogenesis, and reparation. The sequence of events during angiogenesis includes the proteolysis of basement membranes and extracellular matrix, proliferation, migration and alignment of vascular endothelial cells, and the union of two buds into a vascular loop along the lines of traction and tesselation in the extracellular matrix. This change of phenotype seems to be necessary for the growth of many tumours, and for the enlargement of "dormant" metastases. It is influenced by a change of equilibrium between positive and negative regulators of angiogenesis, largely a family of angiogenic peptides with the affinity for heparin (that may be bond in an inactive state within basement membranes and activated by any lesion) on one side, and circulating suppressors of angiogenesis and tumour growth, thrombospondin and angiostatin, on the other side. Clinical evaluation of some of the two dozen known angioinhibitors for the treatment of age-related maculopathy, certain tumours, metastases and malignang ascites, is underway.

Animals↗
PubMed1998

Vascularity in human adrenal cortex.

It has long been postulated that angiogenesis plays important roles in tumor cell proliferation and hormonal secretion of endocrine tumors, including adrenocortical neoplasms. Detailed examination of vascularity, however, has not been reported in adrenocortical tumors. In this study, we quantitatively examined vascularity in normal adrenal, adrenocortical adenoma, and carcinoma using an image analysis system to evaluate vascularity or angiogenesis in these lesions. Vascular density (VD: vessel number/mm2), endothelial area of each vessel (EA: microm2/vessel) and vascular area (VA: the percentage of EA per field) were examined using immunohistochemical analysis of CD34 and the CAS 200 image analysis system. EA and VA of adrenocortical carcinomas (EA, 113.4 +/- 33.1; VA, 6.34 +/- 2.03) were significantly higher than those of adenoma (EA, 66.1 +/- 43.0; VA, 3.11 +/- 1.56) and normal adrenal tissue (EA, 65.4 +/- 26.0; VA, 4.26 +/- 1.19). There were no significant differences in VD among normal cases (702.2 +/- 173.2), adenomas (488.9 +/- 153.2), and carcinomas (573.2 +/- 185.2). These results suggest that adrenocortical carcinoma might be associated with increased endothelial cell proliferation but not with an increased number of intratumoral microvessels. There were no significant differences in these parameters of vascularity examined in the zona glomerulosa, zona fasciculata, and zona reticularis of aldosteronomas, Cushing's adenomas, and nonfunctioning hormonally inactive adenomas nor between specimens from patients who died of the disease and those from patients who did not.

Adrenal Cortex↗
PubMedDate not supplied

Shikonin, an ingredient of Lithospermum erythrorhizon, inhibits angiogenesis in vivo and in vitro.

Angiogenesis is critical for tumor growth and inflammation. Shiunko is a Chinese herbal ointment used for the treatment of burns in Japan. Its main ingredient is the root of Lithospermum erythrorhizon, which had been used for treating tumors and inflammation in China since the 5th century. We report here that shikonin, the main chemical ingredient of L. erythrorhizon is a novel inhibitor of angiogenesis. It inhibited tumor necrosis factor-alpha-induced and B16 melanoma-induced angiogenesis in mice and normal developmental angiogenesis in the yolk-sac membranes of chick embryos. Shikonin also inhibited proliferation and migration of endothelial cells in culture and network formation by endothelial cells on Matrigel in vitro. The dose-responsive study suggests that the mechanism of this inhibitory effect on angiogenesis involves the prevention of network formation by endothelial cells via blocking integrin alpha v beta 3 expression.

Animals↗
PubMed1997

Long-lasting complete inhibition of human solid tumors in SCID mice by targeting endothelial cells of tumor vasculature with antihuman endoglin immunotoxin.

In the present study, we developed an antitumor immunoconjugate that appears to be promising as a novel curative antitumor agent against a variety of human solid tumors. We generated a new antihuman endoglin (EDG) monoclonal antibody (mAb) K4-2C10 (or termed SN6f) that cross-reacts with mouse endothelial cells. Such cross-reactive anti-EDG mAbs have not been reported previously. This mAb was used to target tumor-associated vasculature in SCID mice inoculated with human tumors. No anti-EDG mAb or its immunoconjugates have previously been successfully used for targeting vasculature in vivo. In this study, MCF-7 human breast cancer cells were inoculated s.c. into SCID mice. K4-2C10 did not react with the MCF-7 cells but showed a weak reactivity with mouse endothelial cells. The mAb reacted with the proliferating endothelial cells more strongly than with the quiescent endothelial cells. The mAb exhibited much stronger reactivity (>10-fold) with human endothelial cells than with mouse endothelial cells and reacted strongly with vascular endothelium of tumor-associated blood vessels in a variety of human malignant tissues. Conjugates of K4-2C10 with ricin A chain (RA) and deglycosylated ricin A chain (dgRA) showed a weak but specific cytotoxic activity against murine endothelial cells in vitro; the 50% inhibitory dose of the RA and dgRA conjugates was 54 nm and 29 nm, respectively. Remarkable antitumor efficacy was observed when a small amount (a total of 60 microgram corresponding to 24% of the LD50 dose) of the dgRA conjugate was administered i.v. into SCID mice that had been inoculated s.c. with MCF-7. Unconjugated mAb K4-2C10 was not significantly effective in the inhibition of the tumor growth. The immunotoxin (IT) completely inhibited growth of the tumor in all of the treated mice (n = 8). Furthermore, similar antitumor efficacy was observed when the IT was administered i.v. into the tumor-inoculated SCID mice that had been pretreated with unconjugated K4-2C10 to block the potentially available weak binding sites of normal tissues. The strong therapeutic effects of the IT were reproduced in another set of therapeutic experiments. No significant side effects were observed in the mice. The differences in the tumor growth between the control group and the IT-treated groups were statistically significant. The IT showed antiangiogenic activity in the dorsal air sac method. The results indicate that K4-2C10 IT effectively treated the tumor-bearing mice by selectively inhibiting the tumor-associated blood vessels and by disrupting tumor-associated angiogenesis. The strong antitumor efficacy of the K4-2C10 IT is remarkable in view of the fact that K4-2C10 and its IT showed only a weak reactivity with mouse endothelial cells, and a relatively small amount of the IT was administered i.v. to treat s.c. tumors. We anticipate that the K4-2C10 IT will show much stronger antitumor efficacy and antiangiogenic activity in patients with solid tumors and other angiogenesis-associated diseases. The present results demonstrate for the first time that an anti-EDG mAb or its immunoconjugate can effectively target tumor-associated vasculature in vivo.

Animals↗
PubMed1998

Cell-matrix interactions, alterations with aging, involvement in angiogenesis.

Cell-matrix interactions are mediated primarily by integrins, which are membrane-spanning receptors capable of cell or matrix component recognition and involved in two-way intracellular signal transduction. Aging is associated with quantitative and qualitative changes in matrix macromolecules and the integrins that bind them. These changes translate into alterations in cell-matrix interactions. Integrin expression modifications have also been reported in some diseases.

Aging↗
PubMedDate not supplied

Effect of U-995, a potent shark cartilage-derived angiogenesis inhibitor, on anti-angiogenesis and anti-tumor activities.

BACKGROUND: A potent angiogenesis inhibitor, U-995, has been purified from the cartilage of the blue shark (Prionace glauca). U-995 is composed of two single peptides with molecular mass of 10 and 14 kDa, respectively. MATERIALS AND METHODS: U-995 was designed to study human umbilical vein endothelial cell (HUVEC) migration and proliferation in vitro and angiogenesis induced by TNF alpha in chicken chorioallantoic membrane (CAM). Furthermore, we determined the ability of U-995 to inhibiting tumor cell growth and metastasis. RESULTS: U-995 (15 and 30 micrograms/ml) markedly inhibited HUVEC migration and, at 15-50 micrograms/ml produced a dose-dependent decline in [3H]-thymidine incorporation. 30 and 50 micrograms/ml of U-995, when added to TNF alpha-induced angiogenesis caused discontinuous and disrupted blood vessels. Moreover, U-995 (30 micrograms/ml) markedly prevented collagenase-induced collagenolysis. In addition, when 200 micrograms U-995 was injected i.p. into mice it suppressed sarcoma-180 cell growth and B16-F10 mouse melanoma cell metastasis in vivo. CONCLUSIONS: These results suggest that the anti-angiogenic effects of U-995 may be be due to interference with the proliferation and migration of HUVECs as well as inhibition of collagenolysis, thereby leading to inhibition of both angiogenesis and tumor cell growth.

Allantois↗
PubMed1999

Antiangiogenic effects of camptothecin analogues 9-amino-20(S)-camptothecin, topotecan, and CPT-11 studied in the mouse cornea model.

Angiogenesis has been correlated with increased invasion and metastases in a variety of human neoplasms. Inadequate inhibition of the growth of tumor microvessels by anticancer agents may result in treatment failure, rated clinically as progressive or stable disease. We have investigated the antiangiogenic properties of three camptothecin analogues, 9-amino-20(S)-camptothecin, topotecan, and camptosar (CPT-11), currently under investigation in clinical settings. Angiogenesis was induced by basic fibroblast growth factor in the cornea of inbred Swiss-Webster mice, with the aim of exploring the suppression of neovascularization by the analogues injected into the mice daily over a period of 6 days. The dose range chosen is known to inhibit, in the mouse model, the growth of various human tumor xenografts or murine tumors. The statistical analysis evaluated the association between the area of neoangiogenesis and the dose of the drugs tested and correlated the effects with observed drug toxicity. It was established that, as the drug doses increased, the area of neovascularization decreased, appearing to approximate a negative exponential curve. 9-Amino-20(S)-camptothecin at 6.89 and 8.26 micromol/kg (2.5 and 3.0 mg/kg) and topotecan at 8.31 micromol/kg (3.5 mg/kg), both drugs being delivered over a 6-day period, had statistically significant reduction (47.2-72.5%) of neoangiogenesis and acceptable toxicity. At higher doses of the two analogues, toxic body-weight losses and deaths were observed. CPT-11 showed statistically significant reduction of neoangiogenesis at a dose of 359 micromol/kg (210 mg/kg) delivered over a 6-day course. Unlike camptothecin analogues, the nontoxic dose of vincristine did not induce a statistically significant inhibition of angiogenesis, and there was no dose-dependent escalation of antiangiogenic effects. The results indicate that camptothecins are most likely cytotoxic against two tumor compartments: in addition to tumor cells of epithelial origin, the drugs act against endothelial cells and prevent the growth of the tumor microvessels. We have hypothesized that treatment failure in some patients is due to incomplete or inadequate inhibition of the microvessel growth by camptothecins. Presumably, an intensive inhibition of the remaining tumor microvasculature in such patients could be achieved by combining a camptothecin with another antiangiogenic anticancer agent or with a highly selective angiogenic inhibitor exerting minimal dose-limiting toxicity. Such treatment by a camptothecin plus a less toxic inhibitor of angiogenesis can improve antitumor efficacy. To validate this concept, preclinical studies followed by clinical trials are planned.

Animals↗
PubMed2006

Photodynamic therapy with verteporfin for subfoveal choroidal neovascularization secondary to pathologic myopia: long-term study.

PURPOSE: To assess the safety and effectiveness of photodynamic therapy (PDT) with verteporfin for subfoveal choroidal neovascularization (CNV) secondary to pathologic myopia (PM). METHODS: Sixty-two patients (62 eyes) with PM underwent PDT according to the guidelines of the Verteporfin in Photodynamic Therapy Study. Clinical evaluations performed at all study visits included measurement of best-corrected Snellen visual acuity, slit-lamp biomicroscopy, and fundus fluorescein angiography. Patients were followed up at 1 month and 3 months after treatment and thereafter at 3-month intervals. RESULTS: The final visual acuity of the study patients, after a median follow-up of 31 months, improved by >or=1 Snellen lines in 8 patients (13%), deteriorated in 20 (32%), and remained stable in 34 (55%). The baseline visual acuity was similar in the various study groups. The final mean visual acuity in group A (55 years of age or younger) was 20/80 and significantly (P=0.006) better than that (20/138) in group B (older than 55 years of age). The mean final visual acuity in eyes with higher refractive error at baseline (greater than -17 diopters) was significantly better (P=0.014) than that in eyes with lower refractive error (-6 to -10 diopters). CNV size did not affect visual outcomes. CONCLUSION: PDT preserves vision in patients with CNV associated with PM. Younger patients and eyes with higher refractive error appear more likely to benefit from PDT with verteporfin.

Adult↗
PubMedDate not supplied

Normal and pathological mechanisms in retinal vascular development.

Angiogenesis is a complex biologic process that occurs normally in development and in turnover and remodeling of mature vascular networks. Pathological angiogenesis and neovascularization occur in association with retinal and ocular ischemic diseases, in retinopathy of prematurity and other developmental disorders, and in tumor growth and metastasis. We describe current understanding of cellular and molecular mechanisms of retinal vascular development, highlighting aspects that relate to eye diseases, that provide sites of therapeutic intervention in ophthalmology and that are potential avenues for research.

Animals↗
PubMed2005

Photodynamic therapy with verteporfin for juxtafoveal choroidal neovascularization secondary to pathologic myopia-1-year results of a prospective series.

PURPOSE: To study the efficacy of photodynamic therapy (PDT) with verteporfin in the treatment of juxtafoveal choroidal neovascularization (CNV) secondary to pathologic myopia. METHODS: Prospective, open label, two-centre, noncomparative, interventional case series. Consecutive patients with juxtafoveal CNV associated with pathologic myopia were recruited and treated with a standard regimen of PDT with verteporfin. Patients were being followed up every 3-monthly and retreatment was considered when there was evidence of angiographic leakage. Outcome measures included changes in the mean best-corrected visual acuity (BCVA) at the 1-year follow-up when compared with the baseline, the proportion of patients who had stable (within 1 line) and improved visions. RESULTS: A total of 11 eyes from 11 patients with juxtafoveal CNV secondary to pathologic myopia were recruited and all completed the 1-year follow-up. The mean age at presentation was 44.8 years. The refractive error ranged from -6.0 to -15.0 D (+/-SD was -9.55+/-3.04 D). The logMAR BCVA improved from 0.57 to 0.39 at the 1-year follow-up (Wilcoxon signed-ranks test, P=0.027). The mean improvement was 1.8 lines. Five eyes (45.4%) had BCVA improved by >or=3 lines. None of the treated patients had visual loss of >or=1 line. The mean number of treatments over the 12-month study period was 2.3 sessions. CONCLUSIONS: The results are encouraging, especially on considering the low retreatment rate, stable or improved BCVA in all treated eyes, and consistently good safety profile. Juxtafoveal myopic CNV may be an expanded indication for PDT with verteporfin.

Adult↗
PubMed1981

Rationale for therapy in neovascular glaucoma.

The pathological physiology of neovascular glaucoma is discussed. Various methods of treatment are examined in the light of the theory of causation. The conclusion is drawn that drainage surgery is the most promising of the alternatives. Since conventional drainage surgery is not effective, it is suggested that the long-tube implant of Molteno is the treatment of choice. Results and complications in ten cases are presented.

Atropine↗