Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P39060 (endostatin)
 2,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

As cure rates in childhood acute lymphoblastic leukemia edge toward 80%, the focus of research is shifting to better means of identifying and treating resistant cases. This new emphasis has stimulated progress in several areas. Recent findings suggest that poor early responses to therapy and detection of minimal residual disease at the postremission induction period by immunologic methods are reliable indicators of an adverse prognosis warranting modification of treatment. In this regard, timely administration of intensified chemotherapy, including a second reinduction/intensification phase, may nullify the adverse prognosis conferred by a delayed response to induction therapy. Comparative analysis of survival outcomes in T-cell patients who received chemotherapy or cranial irradiation (12 Gy) to prevent overt leukemia in the central nervous system suggests that the latter modality should be retained for cases with leukocyte counts > 100 x 10(9)/L. Recent innovations in histocompatibility matching, prevention of graft-versus-host disease, and antiviral prophylaxis have enhanced the applicability of hematopoietic stem cell transplantation, making this procedure available to candidates lacking matched sibling donors. Finally, demonstration that acute lymphoblastic leukemia has an angiogenic phase in bone marrow raises the possibility of effective treatment with antiangiogenic agents, such as endostatin. Remaining challenges in the treatment of childhood leukemia include 1) the development of specific and more effective therapy for high-risk cases and 2) the reduction of long-term complications associated with intensive chemotherapy and cranial irradiation.
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PMID:Recent advances in the biology and treatment of childhood acute lymphoblastic leukemia. 974 36

Work begun more than 30 years ago at Children's Hospital in Boston led to the publication of an article on the antiangiogenic properties of two compounds, endostatin and angiostatin (J. Folkman, Nature 1997; 390:404-7). It only took weeks for the medias in the US and then in France and the rest of Europe to stimulate the fervor of patients for this new 'cure' for cancer. Insight into the fundamental role of angiogenesis in locoregional and metastatic development of cancer has been accumulated over the last decades. Factors stimulating tumoral angiogenesis include aFGF, bFGF, VEGF, angiogenin, and other more recently discovered substances. Likewise, factors inhibiting tumoral angiogenesis, including angiostatin, have been identified. Angiostatin is a specific inhibitor of endothelial cell growth that migh appear rapidly in the serum of patients with a primary tumor. Angiostatin could have both local and systemic effects and possibly protect against metastatic dissemination in vivo. The importance of angiogenesis inhibitors was emphasized at the recent meeting of the American Association for Cancer Research (New Orleans March 28-April 1, 1998). To date, at least eleven compounds are being tested. Currently, most are in phase 1 or 2; for the few in phase 3, marketing approval will undoubtedly require several years. It is interesting to note that neither endostatin nor angiostatin are among the list of drugs under clinical assessment, first because these small human proteins are not available in sufficient quantity for therapeutic trials and secondly, because the processes necessary to produce pure and safe compounds remain to be developed. Even after these steps have been accomplished, preclinical evaluations will have to be performed before the first clinical trials could be envisaged. For the time being, antiangiogenesis remains a promising avenue of anti-cancer research but neither endostatin nor angiostatin will be available for human research for several months at least.
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PMID:[Tumor angiogenesis inhibitors: media and scientific aspects]. 976 82

Recently, O'Reilly et al. (O'Reilly, M. S., Holmgren, L., Shing, Y., Chen, C., Rosenthal, R. A., Moses, M., Lane, W. S., Cao, Y., Sage, E. H., and Folkman, J. (1994) Cell 79, 315-328; O'Reilly, M. S., Boehm, T., Shing, Y., Fukai, N., Vasios, G., Lane, W. S., Flynn, E., Birkhead, J. R., Olsen, B. R., and Folkman, J. (1997) Cell 88, 277-285) developed a simple in vitro angiogenesis assay system using bovine capillary endothelial cell proliferation and purified potent angiogenic inhibitors, including angiostatin and endostatin. Using a simple in vitro assay for angiogenesis, we purified a protein molecule that showed anti-endothelial cell proliferative activity from the serum of New Zealand White rabbits, which was stimulated by lipopolysaccharide. The purified protein showed only bovine capillary endothelial cell growth inhibition and not any cytotoxicity. This molecule was identified as a prothrombin kringle-2 domain (fragment-2) using Edman degradation and the amino acid sequence deduced from the cloned cDNA. Both the prothrombin kringle-2 domain released from prothrombin by factor Xa cleavage and the angiogenic inhibitor purified from rabbit sera exhibited anti-endothelial cell proliferative activity. The recombinant rabbit prothrombin kringle-2 domain showed potent inhibitory activity with half-maximal concentrations (ED50) of 2 microg/ml media. As in angiostatin, the recombinant rabbit prothrombin kringle-2 domain also inhibited angiogenesis in the chorioallantoic membrane of chick embryos.
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PMID:Prothrombin kringle-2 domain has a growth inhibitory activity against basic fibroblast growth factor-stimulated capillary endothelial cells. 978 80

Endostatin is a potent angiogenesis inhibitor in vitro and in vivo. We used the yeast Pichia pastoris to express and purify soluble endostatin. It was discovered that metal chelating agents can induce N-terminal degradation of endostatin. We theorized that a metal was removed from endostatin which changed the conformation and allowed a contaminating protease to degrade the N-terminus. Atomic absorption and amino acid analysis of endostatin purified from Pichia pastoris and mammalian cells showed a 1:1 molar ratio of Zn2+ to protein. Ding et al. have shown that histidines 1, 3, 11, and aspartic acid 76 coordinate the Zn2+ atom (1). An H1/3A double, an H11A, and a D76A single mutant of endostatin were not able to regress Lewis lung carcinoma. We conclude that the ability of endostatin to bind Zn2+ is essential for its antiangiogenic activity.
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PMID:Zinc-binding of endostatin is essential for its antiangiogenic activity. 981 68

Tumor angiogenesis is critically important to tumor growth and metastasis. We have shown that pentosan polysulfate (PPS) is an effective inhibitor of heparin-binding growth factors in vitro and can effectively inhibit the establishment and growth of tumors in nude mice. Following completion of our Phase I trial of s.c. administered PPS, we performed a Phase I trial of p.o. administered PPS in patients with advanced cancer to determine the maximum tolerated dose (MTD) and toxicity profile and to search for any evidence for biological activity in vivo. Patients diagnosed with advanced, incurable malignancies who met standard Phase I criteria and who did not have a history of bleeding complications were enrolled, in cohorts of three, to receive PPS p.o. t.i.d., at planned doses of 180, 270, 400, 600, and 800 mg/m2. Patients were monitored at least every 2 weeks with physical exams and weekly with hematological, chemistry, stool hemoccult, and coagulation blood studies, and serum and urine samples for PPS and basic fibroblastic growth factor (bFGF) levels were also taken. The PPS dose was escalated in an attempt to reach the MTD. Eight additional patients were enrolled at the highest dose to further characterize the toxicity profile and biological in vivo effects of PPS. A total of 21 patients were enrolled in the three cohorts of doses 180 (n = 4), 270 (n = 3), and 400 (n = 14) mg/m2. The most severe toxicities seen were grade 3 proctitis and grade 4 diarrhea; however, 20 of the 21 patients had evidence of grade 1 or 2 gastrointestinal (GI) bleeding. These toxicities became evident at a much earlier time point as the dose was increased, but their severities were similar at all dose levels. There were no objective responses, although three patients had prolonged stabilization of previously progressing disease. Pharmacokinetic analysis suggested marked accumulation of PPS upon chronic administration. Serum and urine bFGF levels failed to show a consistent, interpretable pattern; however the data suggested an inverse relationship between PPS and bFGF levels in vivo. A MTD could not be determined using the daily t.i.d. dosing schedule due to the development of grade 3/4 GI toxicity (proctitis) at all dose levels studied. PPS, administered p.o. at doses of 400 mg/m2 t.i.d., did not cause significant systemic toxicity, but most patients developed moderate-to-severe GI toxicity within 1-2 months. The cause of the GI toxicity was unclear, but it was readily reversible upon cessation of the agent. The suggestion of an inverse relationship between PPS and bFGF supports further study of PPS as an antiangiogenic agent. The tested doses and schedule cannot be recommended for further study. Subsequent murine experiments showed PPS to be more effective as an anticancer agent when it is given intermittently. We propose a study of PPS given on a weekly schedule in further clinical trials.
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PMID:Phase I trial of orally administered pentosan polysulfate in patients with advanced cancer. 981 33

Antiangiogenic tumor therapies have recently attracted intense interest for their broad-spectrum action, low toxicity, and, in the case of direct endothelial targeting, an absence of drug resistance. To promote tumor regression and to maintain dormancy, antiangiogenic agents need to be chronically administered. Gene therapy offers a potential way to achieve sustained therapeutic release of potent antiangiogenic substances. As a step toward this goal, we have generated recombinant adeno-associated virus (rAAV) vectors that carry genes coding for angiostatin, endostatin, and an antisense mRNA species against vascular endothelial growth factor (VEGF). These rAAVs efficiently transduced three human tumor cell lines tested. Transduction with an rAAV-encoding antisense VEGF mRNA inhibited the production of endogenous tumor cell VEGF. Conditioned media from cells transduced with this rAAV or with rAAV-expressing endostatin or angiostatin inhibited capillary endothelial cell proliferation in vitro. Antiangiogenic rAAVs may offer a novel gene therapy approach to undermining tumor neovascularization and cancer progression.
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PMID:Adeno-associated virus-mediated delivery of antiangiogenic factors as an antitumor strategy. 986 20

Endostatin is a Mr 20,000 COOH-terminal fragment of collagen XVIII that inhibits the growth of several primary tumors. We report here the cloning and expression of mouse endostatin in both prokaryotic and eukaryotic expression systems. Soluble recombinant protein expressed in yeast (15-20 mg/L) inhibited the proliferation and migration of endothelial cells in response to stimulation by basic fibroblast growth factor. A rabbit polyclonal antibody was raised that showed positive immunoreactivity to the recombinant protein expressed from both systems. Importantly, the biological activity of the mouse recombinant protein could be neutralized by this antiserum in both endothelial proliferation and chorioallantoic membrane assays. Systemic administration of endostatin at 10 mg/kg suppressed the growth of renal cell cancer in a nude mouse model. The inhibition of tumor growth with soluble yeast-produced protein was comparable to that obtained with non-refolded precipitated protein expressed from bacteria. In addition, two closely related COOH-terminal deletion mutants of endostatin were also tested and showed strikingly differing activity. Collectively, these findings demonstrate the expression of a biologically active form of mouse endostatin in yeast, define a role for the molecule in inhibiting endothelial cell migration, extend its antitumor effects to renal cell carcinoma, and provide a formal proof (via the neutralizing antiserum experiments and the mutant data) that endostatin (and not a possible contaminant) acts as an antiangiogenic agent. Finally, the high level expression of mouse endostatin in yeast serves as an endotoxin free, soluble source of protein for fundamental studies on the mechanisms of tumor growth suppression by angiogenesis inhibitors.
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PMID:Endostatin: yeast production, mutants, and antitumor effect in renal cell carcinoma. 989 6

Tumor angiogenesis is critical for the growth of primary cancers above 1-2 mm in diameter. A major vascular growth factor is VEGF, and approaches to inhibit VEGF have shown encouraging results in pre-clinical studies. The mechanisms involved in switching on angiogenesis involve activation of oncogenes and upregulation of the hypoxia-sensing pathway. These provide novel targets for therapy. Many anti-angiogenic drugs are in clinical trial currently and there are problems in assessing these types of drugs if they only cause disease stabilisation. It will be important to develop methods to assess inhibition of vascular growth in vivo. New generations of anti-angiogenesis drugs such as endostatin of angiostatin, which are more potent, may cause tumor regression, but this has not yet been studied in patients. These approaches for advanced disease should be more successful when applied early in an adjuvant situation. This will also require careful monitoring of long-term toxicity.
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PMID:Anti-angiogenesis therapy and strategies for integrating it with adjuvant therapy. 992 71

The "angiogenic switch" and tumor angiogenesis play a critical role in the growth and metastasis of solid tumors. Tumor angiogenesis is regulated by a balance of stimulators (e.g., VEGF, bFGF) and inhibitors of angiogenesis (e.g., angiostatin, endostatin, angiostatic steroids). Measuring angiogenesis (blood vessel density) and/or its main regulators such as VEGF and bFGF in solid tumors, or the levels of these growth factors in the serum or urine provides new and sensitive markers for tumor progression, metastasis and prognosis.
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PMID:The diagnostic and prognostic value of tumor angiogenesis. 1002 73

Based on a homology search with endostatin, the C-terminus 185 aa of collagen XVIII, we report the cloning, expression, and antiangiogenic activity of a 22 kDa human collagen XV fragment, that we have named restin. Restin was expressed in the prokaryotic pET expression system. We have shown that restin inhibits the migration of endothelial cells in vitro but has no effect on the proliferation of these cells. A polyclonal antibody raised against endostatin cross-reacted with restin. Systemic administration of restin suppressed the growth of tumors in a xenograft renal carcinoma model.
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PMID:Antiangiogenic activity of restin, NC10 domain of human collagen XV: comparison to endostatin. 1004 80


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