[Rich66]

Am J Health Syst Pharm. 2009 Jun 1;66(11):999-1013.
Understanding and managing the possible adverse effects associated with bevacizumab.

Shord SS, Bressler LR, Tierney LA, Cuellar S, George A.
College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA. sshord@uic.edu
PURPOSE: The adverse events associated with bevacizumab therapy are characterized, and the underlying pathophysiology, risk factors, frequency, and management of these events are described. SUMMARY: The adverse events associated with bevacizumab include hypertension, proteinuria, thromboembolism, impaired wound healing, bleeding, perforation, reversible leukoencephalopathy syndrome, skin rash, and infusion-related hypersensitivity reactions. Patients should be monitored for these events throughout the course of bevacizumab therapy. Hypertension is by far the most common adverse event associated with bevacizumab. Blood pressure should be routinely monitored, and hypertension should be medically managed with antihypertensive drugs as deemed appropriate during bevacizumab therapy. Patients should be monitored for proteinuria every three to four weeks, and bevacizumab should be discontinued with persistent proteinuria of >2+. Thromboembolic events, impaired wound healing, bowel and nasal septum perforation, and bleeding share similar pathophysiology. Thromboembolic events should be managed in accordance with guidelines established by the American College of Chest Physicians, and bevacizumab should be discontinued for new life-threatening venous or arterial thromboembolism. To minimize the risk of bleeding or impaired wound healing, bevacizumab should be started at least four weeks after surgery or discontinued for at least six to eight weeks before elective surgery. The management of other adverse events is more anecdotal, with relatively few reports of their occurrence with bevacizumab. CONCLUSION: Many of the potential serious complications of bevacizumab can be averted by close monitoring of patient-specific variables, which should be measured at baseline and then at predetermined intervals throughout the course of therapy to maximize patient safety.

PMID: 19451611 [PubMed - indexed for MEDLINE]


Med Oncol. 2010 Mar 6. [Epub ahead of print]
Nasal septum perforation and bevacizumab.

Power DG, Kemeny NE.
Department of Medicine, Gastrointestinal Oncology Division, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10021, USA, powerd@mskcc.org.
The use of targeted/biologic therapies is now commonplace in the treatment of malignant and non-malignant diseases. The novel mode of action of these drugs has resulted in unpredictable and in some cases unexpected side effects. Given the widespread use of bevacizumab and its distinct mode of action, it is important that oncologists report any unexpected adverse events that may be associated with the drug. Herein, we report three cases of spontaneous nasal septum perforation secondary to bevacizumab. We hypothesize an etiology for this rare event and reasons why it is reasonable to rechallenge the patient.

PMID: 20213219 [PubMed - as supplied by publisher]

NOTE: Have encountered patients with the "blow hole" issue on forums.




Integr Cancer Ther. 2006 Mar;5(1):9-29.
Targeting angiogenesis with integrative cancer therapies.

Yance DR Jr, Sagar SM.
Center for Natural Healing, Ashland, Oregon, USA.
An integrative approach for managing a patient with cancer should target the multiple biochemical and physiological pathways that support tumor development while minimizing normal tissue toxicity. Angiogenesis is a key process in the promotion of cancer. Many natural health products that inhibit angiogenesis also manifest other anticancer activities. The authors will focus on natural health products (NHPs) that have a high degree of antiangiogenic activity but also describe some of their many other interactions that can inhibit tumor progression and reduce the risk of metastasis. NHPs target various molecular pathways besides angiogenesis, including epidermal growth factor receptor (EGFR), the HER-2/neu gene, the cyclooxygenase-2 enzyme, the NF-kB transcription factor, the protein kinases, Bcl-2 protein, and coagulation pathways. The herbalist has access to hundreds of years of observational data on the anticancer activity of many herbs. Laboratory studies are confirming the knowledge that is already documented in traditional texts. The following herbs are traditionally used for anticancer treatment and are antiangiogenic through multiple interdependent processes that include effects on gene expression, signal processing, and enzyme activities: Artemisia annua (Chinese wormwood), Viscum album (European mistletoe), Curcuma longa (turmeric), Scutellaria baicalensis (Chinese skullcap), resveratrol and proanthocyanidin (grape seed extract), Magnolia officinalis (Chinese magnolia tree), Camellia sinensis (green tea), Ginkgo biloba, quercetin, Poria cocos, Zingiber officinale (ginger), Panax ginseng, Rabdosia rubescens (rabdosia), and Chinese destagnation herbs. Quality assurance of appropriate extracts is essential prior to embarking on clinical trials. More data are required on dose response, appropriate combinations, and potential toxicities. Given the multiple effects of these agents, their future use for cancer therapy probably lies in synergistic combinations. During active cancer therapy, they should generally be evaluated in combination with chemotherapy and radiation. In this role, they act as biological response modifiers and adaptogens, potentially enhancing the efficacy of the so-called conventional therapies. Their effectiveness may be increased when multiple agents are used in optimal combinations. New designs for trials to demonstrate activity in human subjects are required. Although controlled trials might be preferred, smaller studies with appropriate end points and surrogate markers for antiangiogenic response could help prioritize agents for the larger resource-intensive phase 3 trials.

PMID: 16484711 [PubMed - indexed for MEDLINE]



Biochem Pharmacol. 2010 Feb 11. [Epub ahead of print]
Flavonoids inhibit hypoxia-induced vascular endothelial growth factor expression by a HIF-1 independent mechanism.

Ansó E, Zuazo A, Irigoyen M, Urdaci MC, Rouzaut A, MartÃ*nez-Irujo JJ.
Department of Biochemistry and Molecular Biology, University of Navarra, Pamplona, Spain.
Flavonoids are a group of polyphenolic dietary compounds that have been proposed to possess chemopreventive properties against lung cancer. In this work we analyzed the effect of a group of 20 structurally related flavonoids, including flavones, flavonols and isoflavones, on the production of vascular endothelial growth factor (VEGF) induced by hypoxia in NCI-H157 cells. VEGF is the main regulator of physiological and pathological angiogenesis and is highly stimulated by hypoxia-inducible factor 1 (HIF-1). We found that apigenin, luteolin, fisetin and quercetin inhibited hypoxia-induced VEGF expression in the low micromolar range. Structure-activity relationships demonstrated that flavone derivatives were the most active compounds and that hydroxylation of the A ring at the positions 5 and 7 and of the B ring at the 4' position were important for this activity. Interestingly, only a group of VEGF inhibitors, including apigenin, flavone and 4',7-dihydroxiflavone, reduced the expression of HIF-1alpha under these conditions, whereas others, such as fisetin, luteolin, galangin or quercetin, induced HIF-1alpha expression while reducing those of VEGF. When cells were exposed to hypoxia in the presence of these flavonoids, HIF-1alpha translocated to the nucleus and interacted with p300/CBP, but this complex was transcriptionally inactive. Taken together these findings indicate that flavonoids impair VEGF transcription by an alternative mechanism that did not depend on nuclear HIF levels. We also found that flavonoids suppressed hypoxia-induced STAT3 tyrosine phosphorylation and that this activity correlated with their potency as VEGF inhibitors, suggesting that inhibition of STAT3 function may play a role in this process. Copyright © 2010 Elsevier Inc. All rights reserved.

PMID: 20153296 [PubMed - as supplied by publisher]






Front Biosci. 2007 Sep 1;12:4881-99.
Green tea polyphenols: biology and therapeutic implications in cancer.

Shankar S, Ganapathy S, Srivastava RK.
Department of Biochemistry, University of Texas Health Science Center at Tyler, Tyler, Texas 75703, USA.

FREE TEXT

Multiple lines of evidence, mostly from population-based studies, suggest that green tea consumption is associated with reduced risk of several human malignancies such as cancer and diabetes. Epigallocatechin-3-gallate (EGCG), a major polyphenol found in green tea, is a widely studied chemopreventive agent with potential anticancer activity. Green tea polyphenols inhibit angiogenesis and metastasis, and induce growth arrest and apoptosis through regulation of multiple signaling pathways. Specifically, EGCG regulates expression of VEGF, matrix metalloproteinases, uPA, IGF-1, EGFR, cell cycle regulatory proteins and inhibits NFk B, PI3-K/Akt, Ras/Raf/MAPK and AP-1 signaling pathways, thereby causing strong cancer chemopreventive effects. This review discusses the molecular mechanisms of green tea polyphenols and their therapeutic implications in cancer.

PMID: 17569617 [PubMed - indexed for MEDLINE]



Mol Cancer Ther. 2006 May;5(5):1227-38.
Green tea extract and (-)-epigallocatechin-3-gallate inhibit hypoxia- and serum-induced HIF-1alpha protein accumulation and VEGF expression in human cervical carcinoma and hepatoma cells.

Zhang Q, Tang X, Lu Q, Zhang Z, Rao J, Le AD.
Division of Surgical, Therapeutic and Bioengineering Sciences, Center for Craniofacial Molecular Biology, University of Southern California School of Dentistry, Health Sciences Campus, 2250 Alcazar Street, CSA103, Los Angeles, CA 90033, USA.
Green tea extract and its major component (-)-epigallocatechin-3-gallate (EGCG) exhibit antiangiogenic activities in various experimental tumor models. A growing body of evidence has established that hypoxia-inducible factor-1alpha (HIF-1alpha) and its downstream target, vascular endothelial growth factor (VEGF), play a critical role in tumor angiogenesis. In this study, we investigated the effect of green tea extract and EGCG on HIF-1alpha and VEGF expression in human cervical carcinoma (HeLa) and hepatoma (HepG2) cells. Our results showed that green tea extract and EGCG significantly inhibited hypoxia- and serum-induced HIF-1alpha protein accumulation in these cancer cells but had no effects on HIF-1alpha mRNA expression. Suppression of HIF-1alpha protein by green tea extract and EGCG also resulted in a drastic decrease in VEGF expression at both mRNA and protein levels. The mechanisms of green tea extract and EGCG inhibition of hypoxia-induced HIF-1alpha protein accumulation seem to involve the blocking of both phosphatidylinositol 3-kinase/Akt and extracellular signal-regulated kinase 1/2 signaling pathways and the enhancing of HIF-1alpha protein degradation through the proteasome system. In addition, green tea extract and EGCG inhibited serum-induced HIF-1alpha protein and VEGF expression by interfering with the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling pathways, which play a crucial role in the protein translational machinery cascade. Functionally, green tea extract and EGCG abolished both chemoattractant- and hypoxia-stimulated HeLa cell migration. Our data suggested that HIF-1alpha/VEGF function as therapeutic target for green tea extract and EGCG in the context of cancer chemoprevention and anticancer therapy.

PMID: 16731755 [PubMed - indexed for MEDLINE]


In Vivo. 2005 Jan-Feb;19(1):179-83.
In vivo antitumor effect of ascorbic acid, lysine, proline and green tea extract on human prostate cancer PC-3 xenografts in nude mice: evaluation of tumor growth and immunohistochemistry.

Roomi MW, Ivanov V, Kalinovsky T, Niedzwiecki A, Rath M.
Matthias Rath Research, Cancer Division, Santa Clara, CA 95050, USA.
BACKGROUND: Matrix metalloproteinases (MMPs), vascular endothelial growth factor (VEGF), Ki 67 (proliferative protein) and constituents of ECM play a critical role in angiogenesis, and are crucial in neoplastic invasion and metastasis. Based on the antitumor properties of certain nutrients, we investigated the effect of a diet containing lysine, proline, arginine, ascorbic acid and green tea extract on the growth of tumors induced by implanting human prostate cancer PC-3 cells in athymic nude mice and on the expression of MMPs, VEGF, Ki 67 and fibronectin in these tumors, as well as the production of mucin (by PAS staining). MATERIALS AND METHODS: Male nude mice (n =12) were inoculated with 3x10(6) prostate cancer PC-3 cells and randomly divided into two groups; Group A was fed a regular diet and Group B was fed a regular diet supplemented with 0.5% of the nutrient mixture (NM). Four weeks later, tumors were excised, weighed and processed for histology. RESULTS: The results showed inhibition of tumor growth in Group B. Histological studies revealed inhibition of MMP-9 and VEGF secretion and mitosis in Group B tissues. CONCLUSION: Nutrient supplementation strongly suppressed the growth of tumors without any adverse effects in nude mice, suggesting strong potential as an anticancer agent.

PMID: 15796171 [PubMed - indexed for MEDLINE]



Carcinogenesis vol.28 no.4 pp.858–864, 2007
doi:10.1093/carcin/bgl205

Apigenin inhibits tumor angiogenesis through decreasing HIF-1a and VEGF expression

FULL TEXT(PDF)

Jing Fang1, Qiong Zhou1, Ling-Zhi Liu1, Chang Xia2,
Xiaowen Hu1, Xianglin Shi1 and Bing-Hua Jiang1,2,
1The Institute for Nutritional Sciences, Shanghai Institute for Biological
Sciences, Chinese Academy of Sciences, Shanghai 200031, China and
2Mary Babb Randolph Cancer Center, Department of Microbiology,
Immunology and Cell Biology, West Virginia University, Morgantown,
WV 26506, USA
To whom correspondence should be addressed.
Email: bhjiang@hsc.wvu.edu
Apigenin is a non-toxic dietary flavonoid with anti-tumor properties. We recently showed that apigenin-inhibited hypoxia-inducible factor-1 (HIF-1) and vascular endothelial growth factor (VEGF) expression in human ovarian
cancer cells under normoxic condition. However, the effect of apigenin in angiogenesis remains to be elucidated. Angiogenesis is the formation of new blood vessels and is required for tumor growth and metastasis. In this study, we showed that apigenin-inhibited expression of HIF-1 and VEGF in different cancer cells under both normoxic and hypoxic conditions. We demonstrated that apigenin significantly inhibited tumor angiogenesis in vivo, by using both the chicken chorioallantoic membrane and Matrigel
plug assays. The inhibition of tumor angiogenesis was associated with the decrease of HIF-1 and VEGF in tumor tissues. Taken together, our results show that apigenin suppresses tumor angiogenesis through HIF-1 and VEGF
expression.

Quote:

In this study, we tested several human cancer cells including prostate cancer cells PC-3, DU145 and LNCaP, breast cancer cell MCF-7, and colon cancer cell HCT-8. PC-3 and DU145 cells produced high levels of HIF-1a and VEGF under normoxic conditions (Figure 1A and B). Apigenin inhibited expression of HIF-1a and VEGF in these cells (Figure 1A and B). We found that apigenin inhibited VEGF transcriptional activation through HIF-1a expression (Figure 1D and E). During tumor growth, there is low oxygen environment inside the tumor. Therefore, it is interesting to know whether apigenin could inhibit HIF-1a and VEGF expression induced by hypoxia. Under hypoxia condition, accumulation of HIF-1a and VEGF proteins was observed in PC-3 cells and addition of apigenin suppressed hypoxia-induced HIF-1a and VEGF expression (Figure 1C). Similarly, the induction of HIF-1a and VEGF by hypoxia was abrogated in several different cancer cells by
apigenin treatment (Figure 2). These results suggest that apigenin inhibits HIF-1a and VEGF expression under both normoxic and hypoxic conditions in different cancer cells.

Quote:

To assess the effects of apigenin on tumor angiogenesis, we performed angiogenesis assay in vivo using two different assay systems. The results showed that apigenin is a potent inhibitor of tumor-induced angiogenesis (Figures 4 and 5). Apigenin also inhibited expression of HIF-1a and VEGF in tumor tissues (Figure 4C and D), suggesting that apigenin inhibits angiogenesis through HIF-1a and VEGF expression.

Mol Carcinog. 2008 Sep;47(9):686-700.
Inhibition of HIF-1 alpha and VEGF expression by the chemopreventive bioflavonoid apigenin is accompanied by Akt inhibition in human prostate carcinoma PC3-M cells.

Mirzoeva S, Kim ND, Chiu K, Franzen CA, Bergan RC, Pelling JC.
Department of Pathology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois 60611, USA.
Progression of cancer leads to hypoxic solid tumors that mount specific cell signaling responses to low oxygen conditions. An important objective of anti-cancer therapy is the development of new drugs that suppress hypoxic responses in solid tumors. Apigenin is a natural flavone that has been shown to have chemopreventive and/or anti-cancer properties against a number of tumor types. However, the mechanisms underlying apigenin's chemopreventive properties are not yet completely understood. In this study, we have investigated the effects of apigenin on expression of hypoxia-inducible factor-1 (HIF-1) in human metastatic prostate PC3-M cancer cells. We found that hypoxia induced a time-dependent increase in the level of HIF-1alpha subunit protein in PC3-M cells, and treatment with apigenin markedly decreased HIF-1alpha expression under both normoxic and hypoxic conditions. Further, apigenin prevented the activation of the HIF-1 downstream target gene vascular endothelial growth factor (VEGF). We then showed that apigenin inhibited expression of HIF-1alpha by reducing stability of the protein as well as by reducing the level of HIF-1alpha mRNA. We also found that apigenin inhibited Akt and GSK-3beta phosphorylation in PC3-M cells. Further experiments demonstrated that constitutively active Akt blunted the effect of apigenin on HIF-1alpha expression. Taken together, our results identify apigenin as a bioflavonoid that inhibits hypoxia-activated pathways linked to cancer progression in human prostate cancer, in particular the PI3K/Akt/GSK-3 pathway. Further studies on the mechanism of action of apigenin will likely provide new insight into its applicability for pharmacologic targeting of HIF-1alpha for cancer therapeutic or chemopreventive purposes.

PMID: 18240292 [PubMed - indexed for MEDLINE]





MAbs. 2010 Mar 25;2(2). [Epub ahead of print]
Anti-tumor effect of CT-322 as an adnectin inhibitor of vascular endothelial growth factor receptor-2.

Mamluk R, Carvajal IM, Morse BA, Wong H, Abramowitz J, Aslanian S, Lim AC, Gokemeijer J, Storek MJ, Lee J, Gosselin M, Wright MC, Camphausen RT, Wang J, Chen Y, Miller K, Sanders K, Short S, Sperinde J, Prasad G, Williams S, Kerbel R, Ebos J, Mutsaers A, Mendlein JD, Harris AS, Furfine ES.
Adnexus, A Bristol Myers Squibb R&D Company, Waltham, MA, USA.
CT-322 is a new anti-angiogenic therapeutic agent based on an engineered variant of the tenth type III domain of human fibronectin, i.e., an Adnectin(TM), designed to inhibit vascular endothelial growth factor receptor (VEGFR)-2. This PEGylated Adnectin was developed using an mRNA display technology. CT-322 bound human VEGFR-2 with high affinity (K(D), 11 nM), but did not bind VEGFR-1 or VEGFR-3 at concentrations up to 100 nM, as determined by surface plasmon resonance studies. Western blot analysis showed that CT-322 blocked VEGF-induced phosphorylation of VEGFR-2 and mitogen-activated protein kinase in human umbilical vascular endothelial cells. CT-322 significantly inhibited the growth of human tumor xenograft models of colon carcinoma and glioblastoma at doses of 15-60 mg/kg administered 3 times/week. Anti-tumor effects of CT-322 were comparable to those of sorafenib or sunitinib, which inhibit multiple kinases, in a colon carcinoma xenograft model, although CT-322 caused less overt adverse effects than the kinase inhibitors. CT-322 also enhanced the anti-tumor activity of the chemotherapeutic agent temsirolimus in the colon carcinoma model. The high affinity and specificity of CT-322 binding to VEGFR-2 and its anti-tumor activities establish CT-322 as a promising anti-angiogenic therapeutic agent. Our results further suggest that Adnectins are an important new class of targeted biologics that can be developed as potential treatments for a wide variety of diseases.

PMID: 20190562 [PubMed - as supplied by publisher]