Search PubMed⌕ Search

Biomedical subjects

J Folkman

Publications and source records attributed to J Folkman.

At least 37 records · Page 2Linked to original sources
PubMed2001

Endostatin inhibits angiogenesis by stabilization of newly formed endothelial tubes.

Endostatin decreased vascular endothelial growth factor (VEGF)-induced formation of endothelial tubes and microvessels sprouting from aortic rings and blocked their network. After cessation of treatment, the survival time of endostatin plus VEGF-treated tubes was approximately doubled in comparison to VEGF alone. Endostatin antibody blocked VEGF-induced endothelial tube formation and disrupted existing tubes. Endostatin immunostaining was localized between endothelium and basement membrane and in inter-endothelial junctions of new, but not of quiescent, blood vessels. In tumors grown in SCID mice, endostatin immunostaining was stronger accompanying blood vessel maturation and was significantly prominent in vessels of tumor marginal zone where angiogenesis is highly active. These data indicate a new antiangiogenic action of endostatin stabilizing and maturating endothelial tubes of newly formed blood vessels. Thus, strategies accelerating vascular stabilization and maturation could be promising in tumor therapy.

Angiogenesis Inhibitors↗
PubMed2001

Vascular endothelial growth factor expression and tumor angiogenesis are regulated by androgens in hormone responsive human prostate carcinoma: evidence for androgen dependent destabilization of vascular endothelial growth factor transcripts.

PURPOSE: The hormonally regulated growth of some human carcinomas represents an important therapeutic target. We report that androgens modulate the angiogenic activity of hormone responsive human prostate cancer. MATERIALS AND METHODS: To define further the critical mechanisms underlying hormone responsiveness we examined the angiogenic mediator, vascular endothelial growth factor messenger (m) RNA and protein in response to androgens in vitro as well as the angiogenic response of xenografts of human prostate cancer after androgen withdrawal in vivo. RESULTS: In vitro androgen deprivation of LnCaP prostate cancer cells led to decreased vascular endothelial growth factor mRNA and protein expression as well as a 5-fold destabilization in vascular endothelial growth factor mRNA transcripts. In addition, androgen withdrawal inhibited the hypoxic induction of vascular endothelial growth factor mRNA. In mice bearing LnCaP tumors castration resulted in a rapid decrease in mRNA expression and markedly reduced tumor neovascularization. CONCLUSIONS: These findings implicate sex steroids as an important stimulus for vascular endothelial growth factor regulation in hormone sensitive tumors and demonstrate the reversal of neovascularization after hormone withdrawal as an early event in the tumor response to therapy.

Androgens↗
PubMed2001

Angiogenesis research: guidelines for translation to clinical application.

Angiogenesis research is being translated to the clinic. Certain guidelines may facilitate this effort. Recruitment of endothelial cells by a tumor is an early event in angiogenesis, a process regulated at genetic and epigenetic levels. The microvascular endothelial cell has become an important second target in cancer therapy. Angiogenesis inhibitors are either "direct" or "indirect" and their optimal dosing depends on a different logic than conventional chemotherapy. Conversely, antiangiogenic scheduling of chemotherapy can by-pass drug resistance. Like all solid tumors, hematologic malignancies are angiogenesis-dependent. Further, angiogenesis is modulated by proteins and cells from the hematopoietic and hemostatic systems. Clinical testing of angiogenesis inhibitors has accentuated the need for surrogate markers of tumor angiogenesis activity. Microvessel density, so valuable as a prognostic indicator of metastatic risk, cannot determine efficacy of an angiogenesis inhibitor. In the future, angiogenesis inhibitors may be added to chemotherapy or to radiotherapy, or to other modalities. Also, combinations of angiogenesis inhibitors may be administered together.

Angiogenesis Inhibitors↗
PubMed2000

Efficacy of antiangiogenic therapy with TNP-470 in superficial and invasive bladder cancer models in mice.

OBJECTIVES: To evaluate the efficacy of antiangiogenic therapy with O-(chloracetyl-carbamoyl) fumagillol (TNP-470) in a superficial and an invasive bladder cancer model in mice. The control of recurrent superficial and metastatic bladder cancer constitutes a major problem in urologic practice. Although the established therapies for these cases (immunotherapy, chemotherapy, and radiation therapy) have improved during the previous decades, further improvement and the reduction of existing side effects are needed. The inhibition of angiogenesis represents a new concept in cancer therapy. METHODS: We evaluated the in vitro effect of TNP-470 on the proliferation of bovine capillary endothelial cells (BCE), the superficial transitional cell carcinoma (TCC) cell line (KK-47), and the invasive TCC cell line (MGH-U1). To evaluate the in vivo effect of TNP-470 on the growth of advanced TCCs, both cell lines were injected subcutaneously into SCID mice. When tumors grew to a size of 100 to 200 mm(3), therapy either with TNP-470 or phosphate-buffered saline was initiated. RESULTS: TNP-470 strongly inhibited endothelial cell proliferation in vitro. The in vitro proliferation of both bladder carcinoma cell lines was also inhibited by TNP-470. However, the doses inhibitory to bladder carcinoma cells were 100-fold higher than the doses that were effective in the inhibition of endothelial cell proliferation. In vivo, TNP-470 significantly inhibited the growth of advanced KK-47 (67%) and MGH-U1 (68%) tumors in SCID mice. CONCLUSIONS: Our results indicate that antiangiogenic therapy with TNP-470 is equally effective in advanced superficial and invasive bladder carcinoma models in mice. When our results are taken together with the reports of other laboratories, TNP-470 appears to be a promising candidate as a tumor suppressor in superficial and invasive bladder cancer.

Angiogenesis Inhibitors↗
PubMed2000

Urinary basic fibroblast growth factor: a noninvasive marker of progressive cystic renal disease in a child.

Autosomal recessive polycystic kidney disease (ARPKD) is a hereditary condition with an estimated incidence of 1 in 20,000 live births. Various growth factors have been implicated in the causation of this disease. We describe a child with ARPKD whose levels of urinary basic fibroblast growth factor (bFGF) were markedly elevated. The concentrations of bFGF increased further following right nephrectomy, in response to the compensatory growth of the remaining kidney. We hypothesize that measurement of urinary bFGF may be useful as a noninvasive marker to assess progression of cystic renal development.

Adult↗
PubMed2000

Antitumor activity of endostatin against carcinogen-induced rat primary mammary tumors.

Endostatin, a Mr 20,000 fragment of collagen XVIII, potently inhibits the growth of experimental tumors implanted in mice. Here we report the cloning, expression, and antitumor activity of the rat form of endostatin. When tested on breast carcinomas arising in female virgin rats after intragastric administration of 9,10-dimethyl-1,2-benzanthracene (DMBA), endostatin induced significant inhibition of mammary tumor growth in all of the treated rats during a 4-week treatment period without signs of systemic toxicity. Interestingly, this arrest of tumor growth persisted throughout a four-week off-therapy period. Moreover, endostatin was effective in counteracting the development of multiple primary tumors. These results confirm that rat endostatin is a potent anticancer agent in a carcinogen-induced, spontaneously arising rat breast cancer model. It not only stops the growth of existing tumors but also decreases the incidence of the development of multiple neoplastic lesions.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2000

Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer.

To reveal the antiangiogenic capability of cancer chemotherapy, we developed an alternative antiangiogenic schedule for administration of cyclophosphamide. We show here that this antiangiogenic schedule avoided drug resistance and eradicated Lewis lung carcinoma and L1210 leukemia, an outcome not possible with the conventional schedule. When Lewis lung carcinoma and EMT-6 breast cancer were made drug resistant before therapy, the antiangiogenic schedule suppressed tumor growth 3-fold more effectively than the conventional schedule. When another angiogenesis inhibitor, TNP-470, was added to the antiangiogenic schedule of cyclophosphamide, drug-resistant Lewis lung carcinomas were eradicated. Each dose of the antiangiogenic schedule of cyclophosphamide induced the apoptosis of endothelial cells within tumors, and endothelial cell apoptosis preceded the apoptosis of drug-resistant tumor cells. This antiangiogenic effect was more pronounced in p53-null mice in which the apoptosis of p53-null endothelial cells induced by cyclophosphamide was so vigorous that drug-resistant tumors comprising 4.5% of body weight were eradicated. Thus, by using a dosing schedule of cyclophosphamide that provided more sustained apoptosis of endothelial cells within the vascular bed of a tumor, we show that a chemotherapeutic agent can more effectively control tumor growth in mice, regardless of whether the tumor cells are drug resistant.

Animals↗
PubMed2000

Bone marrow in polycythemia vera, chronic myelocytic leukemia, and myelofibrosis has an increased vascularity.

Several studies have emphasized the significance of neoangiogenesis for tumor growth and progression, but few have focused on malignant hematological disorders. We studied vascular density and architecture in bone marrow samples of patients with chronic myeloproliferative disease (MPD). Vascular structures were immunostained (for von Willebrand factor/FVIII-RAG, CD 31/PECAM or Ulex europeus I for vessels and for vascular endothelial growth factor, VEGF) in samples from patients with polycythemia vera (PV) (n = 7), chronic myelocytic leukemia (CML) (n = 9), and myelofibrosis (MF) (n = 6) when diagnosed and were compared with normal bone marrow specimens (n = 9). We observed that the mean (+/- SD) vessel count per high-power microscopy field (HPF) was 5.3 (+/- 2.1) in normal bone marrow, 5.9 (+/- 2.1) in PV, 10.8 (+/- 3.2) in CML, and 14.4 (+/- 5.5) in MF (P < 0.001 for CMP and MF versus controls). Confocal microscopy, including three-dimensional reconstructions of the blood vessel architecture, confirmed this increased vessel density and revealed tortuous vessel architecture and increased branching in the MPD, particularly in CML and MF. Furthermore, the number of VEGF-positive bone marrow cells was increased in CML and, particularly, in MF. Numbers of VEGF-positive cells and vessels per HPF correlated significantly (r = 0.41; P = 0. 037). Thus the myeloproliferative diseases PV, CML, and MF exhibit neoangiogenesis that is related to diagnosis.

Aged↗
PubMed1999

The generation of endostatin is mediated by elastase.

Endostatin, a potent inhibitor of angiogenesis and tumor growth, is a COOH-terminal fragment of collagen XVIII derived through cleavage of an Ala-His linkage by an as yet unidentified endostatin-processing enzyme. Endostatin was originally isolated from the conditioned medium of hemangioendothelioma (EOMA) cells. By investigating the processing of collagen XVIII to endostatin by EOMA cells, we show here that the generation of endostatin can be mediated by an elastase activity. We also show that several members of the elastase family can act as an endostatin-processing enzyme by specifically cleaving the Ala-His linkage and releasing endostatin from a precursor molecule. We further suggest that the generation of endostatin from collagen XVIII is at least a two-step process, involving a metal-dependent early step and an elastase activity-dependent final step.

Collagen↗
PubMed1999

Regulation of angiostatin production by matrix metalloproteinase-2 in a model of concomitant resistance.

We have previously reported the identification of the endogenous angiogenesis inhibitor angiostatin, a specific inhibitor of endothelial cell proliferation in vitro and angiogenesis in vivo. In our original studies, we demonstrated that a Lewis lung carcinoma (LLC-LM) primary tumor could suppress the growth of its metastases by generating angiostatin. Angiostatin, a 38-kDa internal fragment of plasminogen, was purified from the serum and urine of mice bearing LLC-LM, and its discovery provides the first proven mechanism for concomitant resistance (O'Reilly, M. S., Holmgren, L., Shing, Y., Chen, C., Rosenthal, R. A., Moses, M. A., Lane, W. S., Cao, Y., Sage, E. H., and Folkman, J. (1994) Cell 79, 315-328). Subsequently, we have shown that systemic administration of angiostatin can regress a wide variety of malignant tumors in vivo. However, at the time of our initial discovery of angiostatin, the source of the protein was unclear. We hypothesized that the tumor or stromal cells might produce an enzyme that could cleave plasminogen sequestered by the primary tumor into angiostatin. Alternatively, we speculated that the tumor cells might express angiostatin. By Northern analysis, however, we have found no evidence that the tumor cells express angiostatin or other fragments of plasminogen (data not shown). We now report that gelatinase A (matrix metalloproteinase-2), produced directly by the LLC-LM cells, is responsible for the production of angiostatin, which suppresses the growth of metastases in our original model.

Angiostatins↗
PubMed1999

Tumor development under angiogenic signaling: a dynamical theory of tumor growth, treatment response, and postvascular dormancy.

The effects of the angiogenic inhibitors endostatin, angiostatin, and TNP-470 on tumor growth dynamics are experimentally and theoretically investigated. On the basis of the data, we pose a quantitative theory for tumor growth under angiogenic stimulator/inhibitor control that is both explanatory and clinically implementable. Our analysis offers a ranking of the relative effectiveness of these inhibitors. Additionally, it reveals the existence of an ultimate limitation to tumor size under angiogenic control, where opposing angiogenic stimuli come into dynamic balance, which can be modulated by antiangiogenic therapy. The competitive influences of angiogenically driven growth and inhibition underlying this framework may have ramifications for tissue size regulation in general.

Angiogenesis Inhibitors↗