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Anti-VEGF agents confer survival advantages to tumor-bearing mice by improving cancer-associated systemic syndrome.

ABSTRACT: The underlying mechanism by which anti-VEGF agents prolong cancer patient survival is poorly understood. We show that in a mouse tumor model, VEGF systemically impairs functions of multiple organs including those in the hematopoietic and endocrine systems, leading to early death. Anti-VEGF antibody, bevacizumab, and anti-VEGF receptor 2 (VEGFR-2), but not anti-VEGFR-1, reversed VEGF-induced cancer-associated systemic syndrome (CASS) and prevented death in tumor-bearing mice. Surprisingly, VEGFR2 blockage improved survival by rescuing mice from CASS without significantly compromising tumor growth, suggesting that "off-tumor" VEGF targets are more sensitive than the tumor vasculature to anti-VEGF drugs. Similarly, VEGF-induced CASS occurred in a spontaneous breast cancer mouse model overexpressing neu. Clinically, VEGF expression and CASS severity positively correlated in various human cancers. These findings define novel therapeutic targets of anti-VEGF agents and provide mechanistic insights into the action of this new class of clinically available anti-VEGF cancer drugs.

SUBMITTER: Xue Y

PROVIDER: S-EPMC2587583 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Anti-VEGF agents confer survival advantages to tumor-bearing mice by improving cancer-associated systemic syndrome.

Xue Yuan Y Religa Piotr P Cao Renhai R Hansen Anker Jon AJ Lucchini Franco F Jones Bernt B Wu Yan Y Zhu Zhenping Z Pytowski Bronislaw B Liang Yuxiang Y Zhong Weide W Vezzoni Paolo P Rozell Björn B Cao Yihai Y

Proceedings of the National Academy of Sciences of the United States of America 20081118 47

The underlying mechanism by which anti-VEGF agents prolong cancer patient survival is poorly understood. We show that in a mouse tumor model, VEGF systemically impairs functions of multiple organs including those in the hematopoietic and endocrine systems, leading to early death. Anti-VEGF antibody, bevacizumab, and anti-VEGF receptor 2 (VEGFR-2), but not anti-VEGFR-1, reversed VEGF-induced cancer-associated systemic syndrome (CASS) and prevented death in tumor-bearing mice. Surprisingly, VEGFR2 ...[more]

PMID: 19017793

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Project description:The cytochrome b5 domain containing 2 (CYB5D2; Neuferricin) protein has been reported to bind heme, however, the critical residues responsible for heme-binding are undefined. Furthermore, the relationship between heme-binding and CYB5D2-mediated intracellular functions remains unknown. Previous studies examining heme-binding in two cytochrome b5 heme-binding domain-containing proteins, damage-associated protein 1 (Dap1; Saccharomyces cerevisiae) and human progesterone receptor membrane component 1 (PGRMC1), have revealed that conserved tyrosine (Y) 73, Y79, aspartic acid (D) 86, and Y127 residues present in human CYB5D2 may be involved in heme-binding. CYB5D2 binds to type b heme, however, only the substitution of glycine (G) at D86 (D86G) within its cytochrome b5 heme-binding (cyt-b5) domain abolished its heme-binding ability. Both CYB5D2 and CYB5D2(D86G) localize to the endoplasmic reticulum. Ectopic CYB5D2 expression inhibited cell proliferation and anchorage-independent colony growth of HeLa cells. Conversely, CYB5D2 knockdown and ectopic CYB5D2(D86G) expression increased cell proliferation and colony growth. As PGRMC1 has been reported to regulate the expression and activities of cytochrome P450 proteins (CYPs), we examined the role of CYB5D2 in regulating the activities of CYPs involved in sterol synthesis (CYP51A1) and drug metabolism (CYP3A4). CYB5D2 co-localizes with cytochrome P450 reductase (CYPOR), while CYB5D2 knockdown reduced lanosterol demethylase (CYP51A1) levels and rendered HeLa cells sensitive to mevalonate. Additionally, knockdown of CYB5D2 reduced CYP3A4 activity. Lastly, CYB5D2 expression conferred HeLa cell survival from chemotherapeutic agents (paclitaxel, cisplatin and doxorubicin), with its ability to promote survival being dependent on its heme-binding ability. Taken together, this study provides evidence that heme-binding is critical for CYB5D2 in regulating HeLa cell growth and survival, with endogenous CYB5D2 being required to modulate CYP activities.

Project description:PurposeWe aimed to evaluate the intraoperative application of antimetabolites compared with anti-vascular endothelial growth factor (VEGF) agents with or without antimetabolites in trabeculectomy (Trab) for glaucoma.MethodsRelevant studies were selected through extensive search using PubMed, EMBASE, the Cochrane Library, and Web of Science databases in August 2013. The primary efficacy estimate was measured using weighted mean difference of the percentage of intraocular pressure reduction (IOPR%) from baseline to end-point, and the secondary efficacy estimates were odds ratio (OR) and 95% confidence interval (CI) for complete success rate and qualified success rate. ORs were also used to measure the tolerability estimate for adverse events. Meta-analyses of fixed or random effects models were conducted using RevMan software 5.2 to pool the results of the studies included. Heterogeneity was assessed using Chi(2) test and the I(2) measure.ResultsNine studies enrolling a total of 349 patients were included. The weighted mean difference of IOPR% from baseline was 7.23 (95% CI: 2.57-11.89) for antimetabolites vs. anti-VEGF agents and 3.96 (95% CI: -4.18-12.10) for antimetabolites vs. anti-VEGF agents plus antimetabolites. The pooled ORs comparing antimetabolites with anti-VEGF agents were 2.37 (95% CI: 0.78, 7.21) for the complete success rate and 1.93 (95% CI: 0.52, 7.16) for qualified success rate. The pooled ORs comparing antimetabolites with anti-VEGF agents plus antimetabolites were 1.43 (95% CI: 0.48, 4.29) for the complete success rate and 2.11 (95% CI: 0.12, 37.72) for qualified success rate. The rates of adverse events did not significantly differ between antimetabolites and anti-VEGF agents, with pooled ORs of 0.86 (0.28-2.69) for bleb leakage, 3.01 (0.45-20.10) for choroidal effusion, 0.96 (0.23-3.98) for flat anterior chamber, and 0.90 (0.12-6.60) for hypotony. Further, the rates of adverse events were similar between antimetabolites and anti-VEGF agents plus antimetabolites, with pooled ORs of 0.40 (0.08-2.00) and 8.00 (0.93-68.59) for bleb leakage and hypotony, respectively.ConclusionsIn comparison with anti-VEGF agents, antimetabolites were more effective in lowering IOP in Trab, while the intraoperative application of these two types of agents did not indicate statistically significant differences in the complete success rate, qualified success rate, or incidence of adverse events.

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Anti-VEGF agents confer survival advantages to tumor-bearing mice by improving cancer-associated systemic syndrome.

Publications

Anti-VEGF agents confer survival advantages to tumor-bearing mice by improving cancer-associated systemic syndrome.

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