Improving delivery of antineoplastic agents with anti‐vascular endothelial growth factor therapy

Yang, Anthony D.; Bauer, Todd W.; Camp, E. Ramsay; Somcio, B S Ray; Liu, Wenbiao; Fan, Bingbing; Ellis, Lee M.

doi:10.1002/cncr.20942

Cited by 43 publications

(31 citation statements)

References 67 publications

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“…34 These tumors may also exhibit high interstitial fluid pressure and sluggish perfusion with regions of hypoxia, fibrosis, and acidosis. 35 The abnormal hemodynamic environment of such tumors may render them less sensitive to cancer therapies. 35 It has also been reported that hypoxic squamous carcinoma cells show resistance to radiation therapy, cytostatic drugs, and conventional surgery.…”

Section: Discussionmentioning

confidence: 99%

Prediction of Disease-Free Survival in Patients with Squamous Cell Carcinomas of the Head and Neck Using Dynamic Contrast-Enhanced MR Imaging

Chawla¹,

Kim²,

Loevner³

et al. 2011

AJNR Am J Neuroradiol

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Section: Discussionmentioning

confidence: 99%

Prediction of Disease-Free Survival in Patients with Squamous Cell Carcinomas of the Head and Neck Using Dynamic Contrast-Enhanced MR Imaging

Chawla¹,

Kim²,

Loevner³

et al. 2011

AJNR Am J Neuroradiol

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“…This leads to a decreased uptake of drugs or other therapeutics in tumors. 3,4 When administered as single agents, antiangiogenic drugs have produced only modest objective responses in clinical trials, but overall they have not yielded long-term survival benefits. 5 Combining anti-VEGF treatment with chemotherapy has resulted in an additive or synergistic antitumor effect, presumably by normalization of the tumor vasculature.…”

mentioning

confidence: 99%

Specific imaging of VEGF‐A expression with radiolabeled anti‐VEGF monoclonal antibody

Stollman

Scheer

Leenders

et al. 2008

Intl Journal of Cancer

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Vascular endothelial growth factor‐A (VEGF‐A) is one of the most important angiogenic factors. Here, we studied in a nude mouse model whether the expression of VEGF‐A in a tumor could be imaged with a radiolabeled anti‐VEGF antibody. The humanized anti‐VEGF‐A antibody A.4.6.1. (bevacizumab), which is reactive with all VEGF‐A isoforms, was radiolabeled with In‐111 or with I‐125. The accumulation of the radiolabeled antibodies in VEGF‐A expressing tumors (LS174T) in nude mice was examined in biodistribution studies and by gamma camera imaging. The uptake of the In‐111‐bevacizumab in the tumor at 3 days p.i. was significantly higher than that of I‐125‐bevacizumab (19.4 ± 7.0 %ID/g vs. 9.6 ± 3.3 %ID/g, p = 0.04). Coinjection of an excess unlabeled antibody resulted in a significant decrease in radioactivity concentration in the tumor (<2.9 ± 1.9 %ID/g, p < 0.005), indicating VEGF‐mediated antibody uptake. Highest uptake in the tumor was observed at relatively low antibody protein doses (<3 μg) (20–25 %ID/g). VEGF‐A‐expressing tumors could be clearly visualized on planar scintigraphic images from 24‐hr post injection onwards. In conclusion, VEGF‐A expression in tumors can be visualized specifically with radiolabeled anti‐VEGF‐A‐mAb. © 2008 Wiley‐Liss, Inc.

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“…Several studies have shown that combining therapies targeting the VEGF-VEGFR axis with chemotherapy is more effective on primary and metastatic tumor growth and survival than that achieved with monotherapy (44 -46). Given the vascular permeabilizing effects of VEGF on the tumor vasculature and the VEGFmediated abnormalities in tumor vascular morphology, tortuosity, branching patterns, and blood flow (16,19,46) relative to the normal vasculature, several possible explanations for the beneficial effects of combining VEGF-VEGFRtargeted therapies with chemotherapy are plausible. One possibility is a ''normalization'' of the tumor microenvironment and vasculature by VEGF-VEGFR-directed therapies, increasing the sensitivity of the abnormal tumor vasculature to conventional therapies and leaving more phenotypically normal and functional blood vessels intact within solid tumors, resulting in improved perfusion of the tumor with cytotoxic agents (16, 46 -48).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, it has been shown that anti-VEGF-VEGFR-directed therapies significantly decrease interstitial fluid pressure and restore hydrostatic and oncotic pressure gradients in tumors resulting in significant improvement in tumor perfusion (see refs. 46,48). Improvements in vascular perfusion and delivery of irinotecan to s.c. colorectal tumor xenografts following anti-VEGF antibody administration have been shown preclinically (49) as well as in phase I clinical studies in colorectal cancer patients given bevacizumab before adjuvant chemoradiation therapy (37).…”

Section: Discussionmentioning

confidence: 99%

The effects of the oral, pan-VEGF-R kinase inhibitor CEP-7055 and chemotherapy in orthotopic models of glioblastoma and colon carcinoma in mice

Jones‐Bolin

Zhao²,

Hunter³

et al. 2006

Molecular Cancer Therapeutics

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CEP-7055, a fully synthetic, orally active N,N-dimethylglycine ester of CEP-5214, a C3-(isopropylmethoxy) -fused pyrrolocarbazole with potent pan -vascular endothelial growth factor receptor (VEGFR) kinase inhibitory activity, has recently completed phase I clinical trials in cancer patients. These studies evaluated the antitumor efficacy of CEP-7055 using orthotopic models of glioblastoma and colon carcinoma in combination with temozolomide, and irinotecan and oxaliplatin, respectively, for their effects on primary and metastatic tumor burden and median survival. Chronic administration of CEP-7055 (23.8 mg/kg/dose) and temozolomide resulted in improvement of median survival of nude mice bearing orthotopic human glioblastoma xenografts compared with temozolomide alone (261 versus 192 days, respectively; P V 0.02). Reductions in neurologic dysfunction, brain edema, hemorrhage, and intratumoral microvessel density (CD34 staining) were observed in glioma-bearing mice receiving CEP-7055 alone, temozolomide alone, and the combination of CEP-7055 and temozolomide relative to vehicle and to temozolomide monotherapy. The administration of CEP-7055 in combination with irinotecan (20 mg/kg/dose i.p. Â 5 days), and to a lesser degree with oxaliplatin (10 mg/kg/dose i.v.), showed reductions on primary colon carcinoma and hepatic metastatic burden in the CT-26 tumor model relative to that achieved by irinotecan and oxaliplatin monotherapy. These data show the significant efficacy and tolerability of optimal efficacious doses of CEP-7055 when given in combination with temozolomide and irinotecan relative to monotherapy with these cytotoxic agents in preclinical orthotopic glioma and colon carcinoma models and lend support for the use of these treatment regimens in a clinical setting in patients with glioblastoma and colon carcinoma.

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Improving delivery of antineoplastic agents with anti‐vascular endothelial growth factor therapy

Cited by 43 publications

References 67 publications

Prediction of Disease-Free Survival in Patients with Squamous Cell Carcinomas of the Head and Neck Using Dynamic Contrast-Enhanced MR Imaging

Prediction of Disease-Free Survival in Patients with Squamous Cell Carcinomas of the Head and Neck Using Dynamic Contrast-Enhanced MR Imaging

Specific imaging of VEGF‐A expression with radiolabeled anti‐VEGF monoclonal antibody

The effects of the oral, pan-VEGF-R kinase inhibitor CEP-7055 and chemotherapy in orthotopic models of glioblastoma and colon carcinoma in mice

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