Anti-tumor activity of the novel angiogenesis inhibitor anginex

Dings, Ruud P.M.; Schaft, Daisy W. J. van der; Hargittai, Balázs; Haseman, Judy; Griffioen, Arjan W.; Mayo, Kevin H.

doi:10.1016/s0304-3835(03)00015-6

Cited by 65 publications

(69 citation statements)

References 22 publications

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“…[18][19][20] Apparently, this function of anginex makes tumor tissue more susceptible to radiation and reduces the ability of tumors to recover from radiation, thereby explaining the results of the tumor growth delay assays presented here. In this regard, the in vivo and in vitro studies presented here strongly suggest that anginex actually sensitizes EC to radiation treatment.…”

Section: Discussionmentioning

confidence: 98%

“…As an antiangiogenic agent, effects from anginex on tumor growth are observed only after several days of treatment. 18,20 In combination with radiation, however, effects from anginex are observed on a much shorter time scale. Previous studies with anginex demonstrated that this peptide functions on a shorter time scale by inhibiting EC adhesion to and migration on the extracellular matrix in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…[ 3 H]-thymidine incorporation or the cell counting kit (CCK-8) were used to assess cell proliferation rates relative to untreated cells, as described earlier. 18 All measurements were done in triplicate, and the experiments were done at least 3 times.…”

Section: Cell Culturementioning

confidence: 99%

“…At the same time, the sections were also stained for cell death using a TUNEL (terminal deoxyribonucleotidyl transferase-mediated dUTP-nick-end labeling) assay carried out according to the manufacturer's instructions (in situ cell death detection kit, fluorescein; TUNEL, Roche). The vessel density and architecture, as well as the proliferation and apoptosis, were quantified as described earlier 18,20,26 and summarized in Table I.…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…Recently, we reported the design of anginex, a b-sheet forming peptide 33mer, with potent in vitro 17 and in vivo 18,19 antiangiogenesis activity. Anginex is water soluble, shelf-stable, and nontoxic in animals.…”

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confidence: 99%

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Anginex synergizes with radiation therapy to inhibit tumor growth by radiosensitizing endothelial cells

Dings

Williams

Song

et al. 2005

Intl Journal of Cancer

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We have demonstrated that the designed peptide anginex displays potent antiangiogenic activity. The aim of our study was to investigate the effect of anginex on established tumor vasculature as an adjuvant to radiation therapy of solid tumors. In the MA148 human ovarian carcinoma athymic mouse model, anginex (10 mg/kg) in combination with a suboptimal dose of radiation (5 Gy once weekly for 4 weeks) caused tumors to regress to an impalpable state. In the more aggressive SCK murine mammary carcinoma model, combination of anginex and a single radiation dose of 25 Gy synergistically increased the delay in tumor growth compared to the tumor growth delay caused by either treatment alone. Immunohistochemical analysis also demonstrated significantly enhanced effects of combined treatment on tumor microvessel density and tumor or endothelial cell proliferation and viability. In assessing physiologic effects of anginex, we observed a reduction in tumor perfusion and tumor oxygenation in SCK tumors after 5-7 daily treatments with anginex with no reduction in blood pressure. To test anginex as a radiosensitizer, additional studies using SCK tumors were performed. Three daily i.p. injections of anginex were able to enhance the effect of 2 radiation doses of 10 Gy, resulting in 50% complete responses, whereas the known antiangiogenic agent angiostatin did not enhance the radiation response of SCK tumors. Mechanistically, it appears that anginex functions as an endothelial cell-specific radiosensitizer because anginex showed no effect on in vitro radiosensitivity of SCK or MA148 tumor cells, whereas anginex significantly enhanced the in vitro radiosensitivity of 2 endothelial cell types. This work supports the idea that the combination of the antiangiogenic agent anginex and radiation may lead to improved clinical outcome in treating cancer patients. ' 2005 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Cell Culturementioning

confidence: 99%

Section: Immunohistochemistrymentioning

confidence: 99%

mentioning

confidence: 99%

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Anginex synergizes with radiation therapy to inhibit tumor growth by radiosensitizing endothelial cells

Dings

Williams

Song

et al. 2005

Intl Journal of Cancer

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Combination of anginex gene therapy and radiation decelerates the growth and pulmonary metastasis of human osteosarcoma xenografts

et al. 2018

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Investigate whether rAAV‐anginex gene therapy combined with radiotherapy could decrease growth and pulmonary metastasis of osteosarcoma in mice and examine the mechanisms involved in this therapeutic strategy. During in vitro experiment, multiple treatment regimes (rAAV‐eGFP, radiotherapy, rAAV‐anginex, combination therapy) were applied to determine effects on proliferation of endothelial cells (ECs) and G‐292 osteosarcoma cells. During in vivo analysis, the same multiple treatment regimes were applied to osteosarcoma tumor‐bearing mice. Use microcomputed tomography to evaluate tumor size. Eight weeks after tumor cell inoculation, immunohistochemistry was used to assess the therapeutic efficacy according to microvessel density (MVD), proliferating cell nuclear antigen (PCNA), and terminal‐deoxynucleotidyl transferase‐mediated nick‐end labeling (TUNEL) assays. Metastasis of lungs was also evaluated by measuring number of metastatic nodules and wet weight of metastases. The proliferation of ECs and the tumor volumes in combination therapy group were inhibited more effectively than the other three groups at end point (P < 0.05). Cell clone assay showed anginex had radiosensitization effect on ECs. Immunohistochemistry showed tumors from mice treated with combination therapy exhibited the lowest MVD and proliferation rate, with highest apoptosis rate, as confirmed by IHC staining for CD34 and PCNA and TUNEL assays (P < 0.05). Combination therapy also induced the fewest metastatic nodules and lowest wet weights of the lungs (P < 0.05). rAAV‐anginex combined with radiotherapy induced apoptosis of osteosarcoma cells and inhibited tumor growth and pulmonary metastasis on the experimental osteosarcoma models. We conclude that the primary mechanism of this process may be due to sensitizing effect of anginex to radiotherapy.

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Targeting the CRD F‐face of Human Galectin‐3 and Allosterically Modulating Glycan Binding by Angiostatic PTX008 and a Structurally Optimized Derivative

et al. 2020

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Calix[4]arene PTX008 is an angiostatic agent that inhibits tumor growth in mice by binding to galectin‐1, a β‐galactoside‐binding lectin. To assess the affinity profile of PTX008 for galectins, we used 15N,1H HSQC NMR spectroscopy to show that PTX008 also binds to galectin‐3 (Gal‐3), albeit more weakly. We identified the contact site for PTX008 on the F‐face of the Gal‐3 carbohydrate recognition domain. STD NMR revealed that the hydrophobic phenyl ring crown of the calixarene is the binding epitope. With this information, we performed molecular modeling of the complex to assist in improving the rather low affinity of PTX008 for Gal‐3. By removing the N‐dimethyl alkyl chain amide groups, we produced PTX013 whose reduced alkyl chain length and polar character led to an approximately eightfold stronger binding than PTX008. PTX013 also binds Gal‐1 more strongly than PTX008, whereas neither interacts strongly, if at all, with Gal‐7. In addition, PTX013, like PTX008, is an allosteric inhibitor of galectin binding to the canonical ligand lactose. This study broadens the scope for galectin targeting by calixarene‐based compounds and opens the perspective for selective galectin blocking.

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Anti-tumor activity of the novel angiogenesis inhibitor anginex

Cited by 65 publications

References 22 publications

Anginex synergizes with radiation therapy to inhibit tumor growth by radiosensitizing endothelial cells

Anginex synergizes with radiation therapy to inhibit tumor growth by radiosensitizing endothelial cells

Combination of anginex gene therapy and radiation decelerates the growth and pulmonary metastasis of human osteosarcoma xenografts

Targeting the CRD F‐face of Human Galectin‐3 and Allosterically Modulating Glycan Binding by Angiostatic PTX008 and a Structurally Optimized Derivative

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