Tumor Angiogenesis and Endothelial Cell Modulatory Factors

Desai, Sudhen B.; Libutti, Steven K.

doi:10.1097/00002371-199905000-00002

Cited by 37 publications

(16 citation statements)

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“…The role for VEGF in generating and sustaining new blood vessels appears to be greatest early in tumor development (58,59). Tumor growth, even if initially dependent on VEGF, may become independent after reaching a critical size (60).…”

Section: Discussionmentioning

confidence: 99%

Phase II Study of SU5416, a Small Molecule Vascular Endothelial Growth Factor Tyrosine Kinase Receptor Inhibitor, in Patients with Refractory Multiple Myeloma

Zangari

Anaissie

Stopeck

et al. 2004

Clinical Cancer Research

109

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Purpose: Increased bone marrow angiogenesis and vascular endothelial growth factor (VEGF) levels are of adverse prognostic significance in patients with multiple myeloma (MM). VEGF, a soluble circulating angiogenic molecule, acts via receptor tyrosine kinases, including VEGF receptor 2. SU5416 is a small molecule VEGF receptor 2 inhibitor.Experimental Design: Adult patients with advanced MM were entered on a multicenter phase II study.Results: Twenty-seven patients (median age 69, range 39 -79), median 4 (0 -10) lines of prior therapy, 14 with prior thalidomide therapy, received SU5416 at 145 mg/m 2 twice weekly i.v. for a median of two 4-week cycles (range 0.2-9). Grade 3/4 toxicities were rarely observed; the most frequent was thrombocytopenia (12%). Mild-to-moderate toxicities included nausea (63%), headache (56%), diarrhea, vomiting (both 37%), and fatigue (33%). There were three thromboembolic episodes and five cases of new onset hypertension. Two (7%) patients did not complete the first 4-week cycle of therapy because of adverse events (pneumonia and headache). There were no objective responses. Four patients had disease stabilization for >4 months. A decrease in median VEGF plasma levels was observed in patients with stable disease (n ‫؍‬ 7) compared with patients with progressive disease (n ‫؍‬ 5). Overall median survival was 42 weeks (range 3-92؉).Conclusions: Although SU5416 had minimal clinical activity, signs of biological activity (decrease in plasma VEGF levels) suggest that angiogenic modulation may be of value in patients with MM.

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Section: Discussionmentioning

confidence: 99%

Phase II Study of SU5416, a Small Molecule Vascular Endothelial Growth Factor Tyrosine Kinase Receptor Inhibitor, in Patients with Refractory Multiple Myeloma

Zangari

Anaissie

Stopeck

et al. 2004

Clinical Cancer Research

109

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“…31 Under physiological conditions, angiogenesis is confined to the female reproductive cycle, pregnancy and wound healing and is tightly regulated through a balance between the expression of proangiogenic and antiangiogenic factors. 32 The restriction of tumor cell angiogenesis offers the prospect of selective antiangiogenic therapy with minimal toxicity to normal cells.…”

Section: Discussionmentioning

confidence: 99%

A novel antisense inhibitor of MMP-9 attenuates angiogenesis, human prostate cancer cell invasion and tumorigenicity

et al. 2003

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Androgen deprivation therapy causes a paradoxical elevation of matrix metalloproteinases (MMPs) including MMP-9 resulting in aggressive tumor phenotype in many patients with prostate cancer. In this study, we have evaluated a novel antisense phosphorodiamidate Morpholino oligomer (PMO) targeted against MMP-9 in models of angiogenesis and in human prostate xenograft in athymic mice. The treatment of androgen-independent DU145 human prostate cells with a 21-mer MMP-9 antisense PMO caused a dose-dependent inhibition of cell proliferation compared to scrambled or MMP-2 antisense PMO at similar concentrations. This was associated with decreases in MMP-9 expression, gelatinolytic activity and increased stability of the insulinlike growth factor-binding protein (IGFBP-3), a proapoptotic factor and MMP-9 substrate. In vitro invasion assays revealed a 40-60% inhibition of DU145 cell invasion in the presence of 25 mM MMP-9 antisense PMO. A significant decrease in endothelial cell migration and vascularization was observed in the Matrigel plug assay in mice when treated intraperitoneally with 300 mg/day MMP-9 antisense for 21 days. In the highly vascular DU145 tumor xenografts, MMP-9 inhibition caused decreased tumor growth with regression in 50% of the animals. Histological analysis revealed increased apoptosis and fibrous tissue deposits in the MMP-9 antisense-treated tumors compared to the scrambled and saline controls. No apparent toxicity or mortality was associated with the MMP-9 PMO treatment. In summary, the MMP-9 antisense PMO inhibited in vitro prostate cancer cell proliferation, invasion and in vivo angiogenesis. These data establish the feasibility of developing a site-directed, nontoxic antisense therapeutic agent for inhibiting local invasion and metastasis.

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“…A further approach to antiangiogenic agents involves angiogenic cytokines and their receptors and mAbs directed against either angiogenesis growth factors or endothelial cell proteins [466]. Vitaxin [467] is a 'humanized' mouse mAb directed against the integrin aub3, a protein selectively expressed in the blood vessels of cancers.…”

Section: Angiogenesis Inhibitorsmentioning

confidence: 99%

“…Thus, the synthetic compound thalidomide (109) has both teratogenic and antiangiogenic properties [10,473,474]. The cytokine IL-12 exhibits antiangiogenic activity [466] through its induction of interferon-gamma (IFN-g) which, in turn, induces human IFN-inducible protein 10 (IP-10). IP-10 is a potent inhibitor in vivo of angiogenesis [456,475,476].…”

Section: Angiogenesis Inhibitorsmentioning

confidence: 99%

Critical appraisals of approaches for predictive designs in anticancer drugs

Gnewuch

Sosnovsky

2002

Cellular and Molecular Life Sciences (CMLS)

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The present review provides a critical appraisal of the most important areas in cancer drug research and, ultimately, in clinical oncology and therapy, with emphasis on the elucidation of possible predictive designs for the development of new anticancer drugs. These assessments encompass the well-established anticancer drugs and congeners which have been employed over the years in clinical therapy, and the more recent exploratory agents still requiring further rigorous scrutiny in the clinical environment. These areas mainly include the bioreversible redox carriers, the boron neutron capture compounds, some new mitosis-interactive agents, cell cycle modifiers, biological-response mpdifiers, oncogene inhibitors, drug-antibody conjugates, cancer cell suppression and destruction agents, antiangiogenesis and antimetastasis agents, apoptosis-promoting agents, and gene therapy and vaccines.

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Tumor Angiogenesis and Endothelial Cell Modulatory Factors

Cited by 37 publications

References 0 publications

Phase II Study of SU5416, a Small Molecule Vascular Endothelial Growth Factor Tyrosine Kinase Receptor Inhibitor, in Patients with Refractory Multiple Myeloma

Phase II Study of SU5416, a Small Molecule Vascular Endothelial Growth Factor Tyrosine Kinase Receptor Inhibitor, in Patients with Refractory Multiple Myeloma

A novel antisense inhibitor of MMP-9 attenuates angiogenesis, human prostate cancer cell invasion and tumorigenicity

Critical appraisals of approaches for predictive designs in anticancer drugs

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