New paradigms for the treatment of cancer: The role of anti-angiogenesis agents

Cherrington, Julie M.; Strawn, Laurie M.; Shawver, Laura K.

doi:10.1016/s0065-230x(00)79001-4

Cited by 168 publications

(104 citation statements)

References 125 publications

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“…Since we show in this study that CMDB-7 efficiently blocks in vivo the effects of VEGF produced at high level, we can speculate that this drug could be useful in the case of failure to anti-EGFR treatment. It is believed now that because angiogenesis is a complex and multistage process, treatment with more than one antiangiogenic agent may be beneficial (Cherrington et al, 2000). Also, the neutralisation of angiogenic growth factors, especially VEGF, in tumour with CMDB7 may increase the effects of a variety of antiangiogenic inhibitors .…”

Section: Discussionmentioning

confidence: 99%

Carboxymethyl benzylamide dextran inhibits angiogenesis and growth of VEGF-overexpressing human epidermoid carcinoma xenograft in nude mice

et al. 2003

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Vascular endothelial growth factor (VEGF) expression is elevated in a wide variety of solid tumours. Inhibition of VEGF activities is able to reduce angiogenesis and tumour growth. We have recently shown in vitro that carboxymethyl dextran benzylamide (CMDB7) prevents the binding of VEGF 165 to its cell surface receptors and thus inhibits VEGF activities on endothelial cells. In the present study, we explored the effects of CMDB7 on highly aggressive human epidermoid carcinoma A431 cells known to overexpress epidermal growth factor receptors (EGFRs) and produce a high amount of VEGF and a minor quantity of bFGF. In vitro, CMDB7 blocked the mitogenic activity of A431-conditioned medium on endothelial cells. Concerning A431 cells, CMDB7 inhibited their proliferation and the VEGF 165 binding to them. In vivo, administration of CMDB7 (10 mg kg À1 ) three times per week for 2 weeks inhibited the growth of A431 xenografts in nude mice by 73% as compared to the control group. Immunostaining of endothelial cells with mouse-specific GSL-1 lectin in tumour sections revealed that CMDB7 also inhibited the density of intratumour endothelial cells by 66%. These findings demonstrate that CMDB7 has an efficient antiangiogenic and antitumour action in vivo even when tumour cells produce a high level of VEGF and EGFRs.

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Section: Discussionmentioning

confidence: 99%

Carboxymethyl benzylamide dextran inhibits angiogenesis and growth of VEGF-overexpressing human epidermoid carcinoma xenograft in nude mice

et al. 2003

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“…Research into the mechanisms underlying angiogenesis has resulted in the discovery of a number of potential anti-angiogenic agents and endogenous angiostatic peptides, which are currently undergoing investigation in solid tumours (Bicknell and Harris, 1996;Twardowski and Gradishar, 1997;Cherrington et al, 2000;Eatock et al, 2000;O'Byrne et al, 2000;Talks and Harris, 2000). These include: synthetic matrix metalloproteinase inhibitors (e.g.…”

Section: Discussionmentioning

confidence: 99%

Angiogenesis is an independent prognostic factor in malignant mesothelioma

et al. 2001

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Summary Angiogenesis is essential for tumour growth beyond 1 to 2 mm in diameter. The clinical relevance of angiogenesis, as assessed by microvessel density (MVD), is unclear in malignant mesothelioma (MM). Immunohistochemistry was performed on 104 archival, paraffinembedded, surgically resected MM samples with an anti-CD34 monoclonal antibody, using the Streptavidin-biotin complex immunoperoxidase technique. 93 cases were suitable for microvessel quantification. MVD was obtained from 3 intratumoural hotspots, using a Chalkley eyepiece graticule at × 250 power. MVD was correlated with survival by Kaplan-Meier and log-rank analysis. A stepwise, multivariate Cox model was used to compare MVD with known prognostic factors and the EORTC and CALGB prognostic scoring systems. Overall median survival from the date of diagnosis was 5.0 months. Increasing MVD was a poor prognostic factor in univariate analysis (P = 0.02). Independent indicators of poor prognosis in multivariate analysis were non-epithelial cell type (P = 0.002), performance status > 0 (P = 0.003) and increasing MVD (P = 0.01). In multivariate Cox analysis, MVD contributed independently to the EORTC (P = 0.006), but not to the CALGB (P = 0.1), prognostic groups. Angiogenesis, as assessed by MVD, is a poor prognostic factor in MM, independent of other clinicopathological variables and the EORTC prognostic scoring system. Further work is required to assess the prognostic importance of angiogenic regulatory factors in this disease.

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“…The promise of anti-angiogenic therapy against cancer has led to an explosion of pre-clinical research and a host of anti-angiogenic drugs being evaluated in clinical trials. 70 Unfortunately, early clinical trials have not replicated the results observed from pre-clinical models. The influence of micro-environment on angiogenic factor expression in tumors growing at different sites, along with the fact that the phenotype of endothelial cells varies from tumor to tumor, makes the development of effective and safe anti-angiogenic treatments a difficult task.…”

Section: Microvasculature During Growth Of Primary and Metastatic Brementioning

confidence: 99%

The Natural Progression of Microvasculature in Primary Tumor and Lymph Node Metastases in a Breast Carcinoma Model: Relationship between Microvessel Density, Vascular Endothelial Growth Factor Expression and Metastatic Invasion

Rowe

Tomoda

Strebel

et al. 2004

Cancer Biology & Therapy

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The natural course of tumor microvascularity in rat MTLn3 mammary adenocarcinomas was studied. The relationship between microvessel density (MVD), vascular endothelial growth factor (VEGF) expression, and histopathology was compared in primary and metastatic axillary (ALN) and inguinal lymph node (ILN) tumors over 5-6 tumor doublings. Excised tumors were examined for (i) MVD assessed by immunostaining with anti-CD31 antibody, (ii) VEGF expression assessed by immunostaining with anti-VEGF antibody, and (iii) histopathologic extent of metastatic lymph node invasion. MVD and VEGF scores rose asymptotically with increasing tumor weight in both primary and metastatic tumors. The MVD saturation level was significantly greater for primary tumors (MVD = 22) than for ALNs or ILNs (MVD = 14). Maximal VEGF score was not statistically different between the three kinds of tumors, however the rate of rise in VEGF expression was different. Near-maximal VEGF expression occurred early in tumor growth, preceding microvessel development. Both MVD and VEGF expression in lymph nodes were proportional to the pathology score characterizing increasing metastatic invasion. LNMs limited to the subcapsular sinus had the lowest MVD, indicating an ability to survive without significant vasculature. These findings underscore the differences in angiogenesis between primary tumors and LNMs and have implications for therapy of metastatic cancer. INTRODUCTIONThe development of new blood vessels, a multi-step process known as angiogenesis, is required for both tumor growth and metastatic spread of tumor cells. 1,2 Angiogenesis is initiated by tumor cell-secreted angiogenic factors, particularly members of the vascular endothelial growth factor (VEGF) family. 3 VEGF-A is essential for the normal development and differentiation of the vascular system 4,5 and also induces pathological endothelial cell proliferation and angiogenesis. 3,4,6 VEGF-C and VEGF-D are important in lymphangiogenesis and lymphatic metastasis. [7][8][9] Blocking VEGF ligand-receptor interactions significantly inhibits tumor growth 10-16 thus providing a promising target for therapeutic intervention. [17][18][19] Hypoxia is an important regulator of VEGF. [20][21][22] Since hypoxic areas are commonly present in tumors, upregulation of VEGF leads to angiogenesis and provides a mechanism for tumors to maintain a vascular supply insuring oxygen and nutrients. 23 The transition from a quiescent tumor to an invasive tumor, reflecting a change in the balance between cell death and proliferation, is accompanied by the acquisition of angiogenic properties. 24 This so-called angiogenic switch requires not only upregulation of promoters of angiogenesis, but also downregulation of suppressors. 25 Thus, tumor dormancy and control may be achieved by endogenous angiogenesis inhibitors such as angiostatin, 26 endostatin, 27 and metronomic chemotherapy. 28 Tumor cells can also be stimulated in a paracrine manner by growth factors and other cytokines produced by stromal cells, particula...

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New paradigms for the treatment of cancer: The role of anti-angiogenesis agents

Cited by 168 publications

References 125 publications

Carboxymethyl benzylamide dextran inhibits angiogenesis and growth of VEGF-overexpressing human epidermoid carcinoma xenograft in nude mice

Carboxymethyl benzylamide dextran inhibits angiogenesis and growth of VEGF-overexpressing human epidermoid carcinoma xenograft in nude mice

Angiogenesis is an independent prognostic factor in malignant mesothelioma

The Natural Progression of Microvasculature in Primary Tumor and Lymph Node Metastases in a Breast Carcinoma Model: Relationship between Microvessel Density, Vascular Endothelial Growth Factor Expression and Metastatic Invasion

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