(Avastin: w/Hif-1 inhib, timing concerns in progression, frequency, continuation, w/chemoendocrine, Zoledronic acid, other drugs, Boswellia, Resveratrol, Green Tea, IP6, w/mTOR inhib, CNS, CSC, Sorafenib/Bev intermittent combo, oral motesanib, w/endocrine therapy)
Cell Prolif. 2009 Jun;42(3):317-29. Epub 2009 Mar 31.
The dynamics of tumour-vasculature interaction suggests low-dose, time-dense anti-angiogenic schedulings.
d'Onofrio A,
Gandolfi A,
Rocca A.
Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy.
alberto.donofrio@ifom-ieo-campus.it
OBJECTIVES: The administration schedule appears to be a particularly relevant factor in determining the effectiveness of an antiangiogenic drug. A better quantitative knowledge of the interactions between tumour growth and the development of its vasculature could help to design effective therapies. MATERIAL AND METHODS: Biological and clinical inferences were derived from the analysis of a mathematical model proposed by Hahnfeldt et al. (1999), and some of its variants. In particular, we compared the effect of constant continuous infusion of an anti-angiogenic drug that induces vascular loss, to the effect of periodic, bolus-based therapy.
RESULTS AND CONCLUSIONS: The role of drug elimination rate and of dose fractionation was investigated, and we show that
different schedulings, guaranteeing the same mean value of drug concentration, may exhibit very different long-term responses according to their concentration vs. time profile. For a large class of tumour growth laws, the profiles that approach the constant one are the most effective. This behaviour appears to depend on the 'cooperativity' of the tumour-vasculature interaction and on the functional form of the relationship between tumour growth and vasculature extent. Moreover, we suggest that a therapy approaching constant drug infusion might be advantageous also in the case of cytostatic anti-angiogenic drugs.
PMID: 19438898 [PubMed - indexed for MEDLINE]
J Theor Biol. 2010 Jan 22. [Epub ahead of print]
Chemotherapy of vascularised tumours: Role of vessel density and the effect of vascular "pruning"
d'Onofrio A,
Gandolfi A.
Department of Experimental Oncology, European Institute of Oncology, Via Ripamonti 435, 20141 Milano, Italy.
In this work we propose to model chemotherapy taking into account the mutual interaction between tumour growth and the development of tumour vasculature. By adopting a simple model for this interaction, and assuming that the efficacy of a drug can be modulated by the vessel density, we study the constant continuous therapy, the periodic bolus-based therapy, and combined therapy in which a chemoterapic drug is associated with an anti-angiogenic agent. The model allows to represent the vessel-disrupting activity of some standard chemotherapic drugs, and shows, in the case of constant continuous drug administration, the possibility of multiple stable equilibria. The multistability suggests an explanation for some sudden losses of control observed during therapy, and for the beneficial effect of vascular "pruning" exherted by anti-angiogenic agents in combined therapy. Moreover, in case of periodic therapies in which the drug amount administered per unit time is constant ("metronomic" delivery), the model predicts a response, as function of the bolus frequency, significantly influenced by the extent of the anti-angiogenic activity of the chemotherapic drug and by the dependence of the drug efficacy on the vessel density. Copyright © 2010. Published by Elsevier Ltd.
PMID: 20100496 [PubMed - as supplied by publisher]
Math Med Biol. 2009 Mar;26(1):63-95. Epub 2008 Nov 25.
A family of models of angiogenesis and anti-angiogenesis anti-cancer therapy.
D'Onofrio A,
Gandolfi A.
Epidemiology and Biostatistics Division, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy.
alberto.donofrio@ieo.it
In this paper we propose a class of models that describe the mutual interaction between tumour growth and the development of tumour vasculature and that generalize existing models. The study is mainly focused on the effect of a therapy that induces tumour vessel loss (anti-angiogenic therapy), with the aim of finding conditions that asymptotically guarantee the eradication of the disease under constant infusion or periodic administration of the drug. Furthermore, if tumour and/or vessel dynamics exhibit time delays, we derive conditions for the existence of Hopf bifurcations. The destabilizing effect of delays on achieving the tumour eradication is also investigated. Finally, global conditions for stability and eradication in the presence of delays are given for some particular cases.
PMID: 19033598 [PubMed - indexed for MEDLINE]
Semin Cancer Biol. 2009 Oct;19(5):279-84. Epub 2009 Oct 7.
Cancer stem cells and angiogenesis.
Bjerkvig R,
Johansson M,
Miletic H,
Niclou SP.
NorLux Neuro-Oncology, Department of Biomedicine, University of Bergen, N-5009, Bergen, Norway.
rolf.bjerkvig@biomed.uib.no
Most cancers contain tumor cells that display stem cell-like characteristics. How and when such cells appear in tumors are not clear, but may involve both stochastic as well as hierarchical events. Most likely, tumor cells that display stem cell-like characteristics can undergo asymmetric cell division giving rise to tumor cells that trigger angiogenic programs. As normal stem cells the
cancer stem-like cells seem to adapt to hypoxic environments and will use metabolic pathways that involve increased conversion of glucose to pyruvate and lactate, and a concomitant decrease in mitochondrial metabolism and mitochondrial mass. The molecular pathways responsible for inducing glycolysis are now being explored. These pathways seem to mediate multiple metabolic functions in cancer stem-like cells, leading to a highly migratory and angiogenesis-independent phenotype. Future challenges will be to identify and validate molecular targets involved in anaerobic metabolic pathways active in cancer stem-like cells and to determine how these pathways differ from regulatory pathways involved in normal stem cell function.
PMID: 19818406 [PubMed - in process]
Mol Cancer Ther. 2009 Jul;8(7):1867-77. Epub 2009 Jul 7.
Increased antitumor activity of bevacizumab in combination with hypoxia inducible factor-1 inhibition.
Rapisarda A,
Hollingshead M,
Uranchimeg B,
Bonomi CA,
Borgel SD,
Carter JP,
Gehrs B,
Raffeld M,
Kinders RJ,
Parchment R,
Anver MR,
Shoemaker RH,
Melillo G.
SAIC-Frederick Inc, National Cancer Institue at Frederick, Frederick, MD 21702, USA.
Inhibition of hypoxia inducible factor-1 (HIF-1) is an attractive therapeutic strategy to target the tumor microenvironment. However, HIF-1 inhibitors may have limited activity as single agents and combination therapies may be required. We tested the hypothesis that HIF-1 inhibition in a hypoxic-stressed tumor microenvironment, which could be generated by administration of antiangiogenic agents, may result in a more pronounced therapeutic effect. The activity of bevacizumab, either alone or in combination with the HIF-1alpha inhibitor topotecan, was evaluated in U251-HRE xenografts. Tumor tissue was collected at the end of treatment and changes in tumor oxygenation, angiogenesis, proliferation, apoptosis, HIF-1alpha levels, HIF-1 target genes, and DNA damage were evaluated.
Bevacizumab decreased microvessel-density and increased intratumor-hypoxia, but did not induce apoptosis. Moreover, bevacizumab alone caused a significant increase of HIF-1-dependent gene expression in tumor tissue. Addition of a low dose of daily topotecan to bevacizumab significantly inhibited tumor growth, relative to mice treated with topotecan or bevacizumab alone (P < 0.01). The addition of topotecan to bevacizumab was also associated with profound inhibition of HIF-1 transcriptional activity, significant inhibition of proliferation, and induction of apoptosis. Importantly, DNA damage induced by topotecan alone was not augmented by addition of bevacizumab, suggesting that increased cytotoxic activity did not account for the increased antitumor effects observed.
These results strongly suggest that combination of anti-vascular endothelial growth factor antibodies with HIF-1 inhibitors is an attractive therapeutic strategy targeting in the hypoxic tumor microenvironment.
Hypoxia-Inducible Factor (HIF-1) (concepts and inhibitors)
http://her2support.org/vbulletin/sho...ighlight=Hif-1
Published online 8 April 2009 | Nature 458, 686-687 (2009) | doi:10.1038/458686b
News
Cutting off cancer's supply lines
Targeting the blood vessels that feed tumours is not the silver bullet once hoped for, but refinements to the strategy may suggest further ways to treat the disease. Erika Check Hayden reports.
Erika Check Hayden
Network of blood vessels surrounding a tumour — a potential target for therapy.Network of blood vessels surrounding a tumour — a potential target for therapy.CLOUDS HILL IMAGING LTD/SPl
Drugs that aim to choke off a tumour's blood supply, known as angiogenesis inhibitors, have been hailed as opening a new era in cancer therapy. But a flurry of animal studies suggests that such drugs may in certain situations actually accelerate the spread of cancer.
"We're just finding the limitations of these types of agents in the clinic," says John Ebos, a cancer researcher at the University of Toronto, Canada. "I don't think it's unique — various types of therapies, such as chemotherapy and radiation, also have limitations. It's just a question of how we can overcome it."
This is a key time in the long and controversial history of these drugs. In May, the US Food and Drug Administration (FDA) is expected to decide whether to expand use of bevacizumab, the first angiogenesis inhibitor. This monoclonal antibody, sold as Avastin by South San Francisco-based Genentech, was approved in 2004 for treating metastatic colon cancer in combination with chemotherapy. It has since been approved in the United States and elsewhere for other uses, and on 31 March an FDA advisory committee recommended the drug also be approved for glioblastoma, a deadly brain cancer for which few other treatments are available. The agency's decision is expected in May.
“I think there's been that growing feeling of why aren't they working better, and we're now uncovering some explanations.”
According to regulatory papers filed in January, Genentech may before then reveal results of a clinical trial to test the use of bevacizumab as an 'adjuvant' used with chemotherapy in patients whose colon tumours have been surgically removed. The 2,710-patient phase III trial investigated whether those who take bevacizumab are more likely to survive without recurrence of their disease than patients who do not take the drug.
"There are tens of thousands of patients with early colorectal cancer who don't get Avastin right now," says Geoffrey Porges, an analyst with Sanford C. Bernstein in New York City. Success as an adjuvant therapy "would open up a market at least as large as the current metastatic market", he thinks, noting that trials testing the drug as an adjuvant for other cancers are under way. Last year, the drug racked up $4.8 billion worldwide in sales; its wholesale price is about $50,000 per year of treatment.
The original idea behind bevacizumab and other angiogenesis inhibitors was championed by Judah Folkman of Harvard Medical School. In 1971, Folkman wrote in the New England Journal of Medicine1 that all tumours depend on the constant growth of new blood vessels, a process called angiogenesis, and that blocking it should eliminate the cancer. The popularity of the idea waned in the early 2000s following disappointing results in clinical trials of two anti-angiogenic compounds, angiostatin and endostatin, that were discovered in Folkman's lab. It regained ground when bevacizumab was approved.
Since 2004, two other angiogenesis inhibitors have been approved in major markets worldwide: sunitinib, sold as Sutent by Pfizer, for use in advanced kidney cancer and gastrointestinal stromal tumours, and sorafenib, sold as Nexavar by Bayer, for use in kidney and liver cancer. Both are small-molecule drugs that target kinases, in particular vascular endothelial growth factor, or VEGF, which is also targeted by bevacizumab. Many more such compounds are in late-stage clinical trials (see table).
But these drugs have not been the magic bullet that Folkman envisaged. In major cancers, such as breast and colon, they have helped patients to survive longer when given with chemotherapy, but not when given alone. The drugs seem to grant most patients slower progression and a few extra months of survival — a real benefit, but not a cure.
The tumours fight back
That has led researchers to ask whether the drugs are working as Folkman hypothesized. Some, such as Rakesh Jain of the Massachusetts General Hospital in Boston, have suggested that the drugs "normalize" blood-vessel growth around tumours. Cancer blood vessels are normally leaky and chaotic; by correcting this, angiogenesis inhibitors may turn the vessels into a more efficient pipeline for delivering chemotherapy, Jain suggests.
Some physicians who treat patients with cancer have also noticed that when the disease does return after treatment aimed at angiogenesis, it is more aggressive than in patients not treated with the drugs. Other researchers now have evidence that may validate this observation. In mouse studies, researchers have reported that the drugs can speed the spread of tumours to nearby tissues and distant organs.
Reporting recently in Cancer Cell, two teams investigated the effects of angiogenesis-inhibiting drugs and of knocking out the gene encoding VEGF. One team, led by Douglas Hanahan of the University of California, San Francisco, and Oriol Casanovas of the Catalan Institute of Oncology in Barcelona, Spain, reported that tumours spread faster and more often to both near and distant organs in mice treated with drugs or lacking the VEGF gene2. The other group, led by Robert Kerbel of the University of Toronto, reported similar effects3, and found that in some situations the treated mice actually died earlier than untreated animals.
Kerbel's group further studied how metastasis changed depending on when the drugs were given.
When given either before or long after metastatic tumour cells were injected into the mice, or after primary tumours had been surgically removed, the drugs hastened metastasis. But when given while the mice were still carrying primary tumours — those that had yet to metastasize — the drugs actually helped shrink the tumours. If the data hold true in humans, they suggest that the timing of drug delivery can have a major impact on a patient's response.
“What they're telling us is that there are other targets that need to be considered if you're going to mess with the blood supply.”
A third paper4, published online in Nature Medicine on 22 March, suggested that such effects might also occur for a class of drugs called integrin inhibitors. These block the activity of integrins, which are proteins that trigger angiogenesis, among other things. Researchers led by Kairbaan Hodivala-Dilke at Queen Mary, University of London, studied the effects of two integrin inhibitors, one of which, cilengitide, is in phase III clinical trials to treat brain cancer. They found that, when given in low doses in mice, the drugs paradoxically seemed to promote angiogenesis and tumour growth.
Ebos, the first author on the Kerbel-group paper, says that, taken together, these studies don't mean anti-angiogenesis drugs are a disappointment, simply that they have limitations. "I think there's been that growing feeling of why aren't they working better, and I think we're now uncovering some of the explanations," he says.
For instance, Hanahan and Casanovas's team studied whether choking off some blood vessels, and thereby inducing oxygen deprivation (hypoxia), might be driving the tumours to search elsewhere for sustenance. When they stained cancer cells in mice with a marker for hypoxia, it showed up in the cancer cells of animals treated with angiogenesis inhibitors.
The oxygen connection
To Casanovas, this provides a link to earlier studies indicating that hypoxia can boost tumour invasiveness, and shows that the
lack of oxygen caused by angiogenesis inhibitors actually induces cancerous cells to leave the tumour site in search of it. Casanovas says that his and Kerbel's teams have together found enough evidence to suggest that such effects probably occur with many angiogenesis inhibitors in many different tumour types. "Between us, we have tested five different compounds, including small molecules and antibodies, so we think the effect could be more general than strictly what we've seen in these two papers, and the same thing applies for different types of tumours," Casanovas says.
Donald McDonald, a vascular biologist at the University of California, San Francisco, suggests that the new studies are delivering a broader message. "What they're telling us is that there are other targets [in addition to VEGF] that need to be considered if you're going to mess with the blood supply." Drug companies are already developing compounds that may address some of the problems raised by the papers.
McDonald notes that
researchers six years ago reported5 that hypoxic cancer cells ramped up production of a protein called Met, which binds and activates another protein called hepatocyte growth factor. This growth factor also goes by the name of scatter factor because it triggers cells to move — precisely the effect seen in the Cancer Cell papers. Administered with anti-angiogenesis drugs, Met inhibitors — the focus of development by drug and biotechnology companies — might offset the effects reported in the Cancer Cell papers, McDonald suggests.
And Hodivala-Dilke's team noted that
simply using some drugs differently might improve their effectiveness. Clinical trials of cilengitide have delivered mixed results so far, and the team says its study points to a possible reason for this. They found that integrin inhibitors slowed the degradation of proteins that promote angiogenesis. These longer-lived proteins then recruited cells that make up blood-vessel walls to the tumour site, where they built new blood pipelines to the tumour. Because the effect occurred only at very low doses, the team suggests that the drugs should be delivered continuously, rather than at a high dose followed by drug-free days, as was done in the clinical trials. That way, levels would stay above those that seemed to promote angiogenesis in the study.
Porges says that the new studies have not dampened enthusiasm among drug companies who are developing angiogenesis inhibitors, integrin inhibitors and inhibitors of other growth factors thought to be involved in cancer. They expect that eventually patients will be given combinations of inhibitors, with or without chemotherapy.
Because of this, McDonald says that the angiogenesis-inhibitor story is far from over. "We have learned that what these drugs do is more complicated than the original idea, which was that they would stop tumour growth by stopping blood-vessel growth," he says. "Avastin is chapter one of angiogenesis inhibition, and we're going to move on to chapter two and chapter three. And with each chapter there will be more clinical benefit as we get a better understanding of the underlying biology."
See Editorial, page 679.
*
References
1. Folkman, J. N. Engl. J. Med. 285, 1182–1186 (1971). | PubMed | ISI | ChemPort |
2. P*ez-Ribes, M. et al. Cancer Cell 15, 220–231 (2009). | Article | PubMed |
3. Ebos, J. M. L. et al. Cancer Cell 15, 232–239 (2009). | Article | PubMed |
4. Reynolds, A. R. et al. Nature Med. doi:10.1038/nm.1941 (2009).
5. Pennacchietti, S. et al. Cancer Cell 3, 347–361 (2003). | Article | PubMed | ISI |
Mol Oncol. 2010 Jan 7. [Epub ahead of print]
Targeting of VEGF-dependent transendothelial migration of cancer cells by bevacizumab.
Prager GW,
Lackner EM,
Krauth MT,
Unseld M,
Poettler M,
Laffer S,
Cerny-Reiterer S,
Lamm W,
Kornek GV,
Binder BR,
Zielinski CC,
Valent P.
Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, A-1090 Vienna, Austria.
Cancer progression is often associated with the formation of malignant effusions. Vascular endothelial growth factor (VEGF) is a major regulator of vascular permeability and has been implicated as mediator of tumor progression. We examined the production and secretion of VEGF(165) in various primary cancer cells derived from malignant effusions, and the role of exogenous VEGF(165) as a mediator of effusion formation.
VEGF(165) was constantly secreted by all cultured tumor cells in an mTOR-dependent manner, as it was inhibited by the mTOR inhibitor rapamycin. Secreted VEGF(165) showed functional activity by inducing endothelial leakiness and tumor cell-transendothelial migration in vitro, effects which could be reverted by the anti-VEGF antibody bevacizumab. Thus, mTOR inhibitors as well as bevacizumab should be considered as potential agents in cancer patients suffering from malignant effusions. Copyright © 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
PMID: 20106729 [PubMed - as supplied by publisher]
Breast Cancer Res Treat. 2010 Jan 9. [Epub ahead of print]
Bevacizumab in metastatic breast cancer: a meta-analysis of randomized controlled trials.
Valachis A,
Polyzos NP,
Patsopoulos NA,
Georgoulias V,
Mavroudis D,
Mauri D.
Department of Medical Oncology, University General Hospital of Heraklion, Heraklion, Greece.
Numerous studies have demonstrated that angiogenesis and in particular VEGF over-expression play an essential role in the progression and metastatic potential of breast cancer. Bevacizumab is a humanized recombinant monoclonal antibody that specifically blocks the binding of VEGF to high-affinity receptors and it has been recently used for the treatment of metastatic breast cancer. We conducted a meta-analysis to synthesize available evidence for use of bevacizumab in metastatic breast cancer patients. Systematic review and meta-analysis of available trials. Primary outcomes were overall survival, progression free survival (PFS) and objective response rate (ORR). Five trials were identified with 3,163 eligible patients. Combination of bevacizumab and chemotherapy resulted in a statistically significant improvement in PFS (HR = 0.70, 95% CI 0.60-0.82, P = 9.3 x 10(-6)) and ORR (RR = 1.26, 95% CI 1.17-1.37, P = 9.96 x 10(-9)) compared with chemotherapy alone.
Differences in objective response rates were substantial independently by the type of chemotherapy used, while PFS advantages were observed only for taxanes. The pooled HR for overall survival did not show significant advantage for the use of bevacizumab compared to placebo arm (HR = 0.90, 95% CI 0.80-1.03, P = 0.119). This meta-analysis shows that the addition of bevacizumab to chemotherapy offers meaningful improvement in PFS and ORR in patients with metastatic breast cancer. Bevacizumab treatment might be suggested for treatment of 1st line metastatic breast cancer, but more data are needed until statistical overall survival differences will be documented and firm guideline recommendation could be given.
PMID: 20063120 [PubMed - as supplied by publisher]
J Chemother. 2008 Oct;20(5):632-9.
Bevacizumab in combination with metronomic chemotherapy in patients with anthracycline- and taxane-refractory breast cancer.
Garc*a-Sáenz JA,
Mart*n M,
Calles A,
Bueno C,
Rodr*guez L,
Bobokova J,
Custodio A,
Casado A,
D*az-Rubio E.
Service de Oncolog*a Médica, Hospital Cl*nico San Carlos, Madrid, Spain.
A vascular endothelial growth factor (VEGF) inhibitor might enhance metronomic chemotherapy in previously treated metastatic breast cancer (MBC) patients.
Anthracycline and taxane refractory MBC patients were given cyclophosphamide 50 mg p.o. daily, methotrexate 1 mg/kg i.v. every 14 days, and bevacizumab 10 mg/kg i.v. every 14 days. Trastuzumab was added in HER2-overexpressing tumors. 24 patients were enrolled and 22 were evaluable. All tumors had histologic grade II-III and most patients had > or =2 metastatic sites. After a median follow-up of 7.7 months the response rates were: complete response (CR) 0%, partial response (PR) 31.8% (95% CI 13.9- 54.9%), stable disease for >or =24 weeks (SD) 31.8% (95% CI 13.9-54.9%). Clinical benefit (CB= CR + PR + SD>24w) 63.6% (95% CI 40.7-82.8%). Median progression-free survival (PFS) was 7.5 months; overall survival (OS) was 13.6 months. HER2-overexpressing or high proliferative-index tumors had better 6-month PFS (75% vs. 34% in HER-negative tumors, P = 0.043; 67% vs. 0% in Ki-67 > or =20% tumors, P = 0.015). Adverse effects were mild.
The combination of bevacizumab and a metronomic-based chemotherapy was effective, well tolerated and provided clinical benefit in heavilytreated MBC patients.
PMID: 19028628 [PubMed - indexed for MEDLINE]
http://www.cancerfacts.com/Home_News...CancerTypeId=4
Avastin® prolongs progression-free survival for certain cancer types
Source: (cancerfacts.com)
Friday, December 18, 2009
Second of four summaries of studies presented at the San Antonio Breast Cancer conference Dec. 9-13
SAN ANTONIO – Dec. 18, 2009 – In a study of advanced breast cancer, researchers have found that taking a drug that blocks blood vessel growth after chemotherapy significantly lengthened the time the tumor growth is halted in women whose tumors do not over produce the HER2 protein.
The RIBBON-2 clinical trial is the third to show that adding bevacizumab (Avastin®) to chemotherapy extends progression-free survival in women whose breast cancer has spread, or metastasized to other parts of the body.
"Potentially, we have another biologic agent that can improve the survival or at least the progression-free survival of women with metastatic breast cancer," said Dr. Adam Brufsky, associate professor of medicine, associate chief of hematology-oncology and associate director of clinical investigation, University of Pittsburgh Cancer Institute.
"Clearly, this may be an indication to use bevacizumab in this setting, but we really have to consider the results of this trial in terms of how best to use these drugs in metastatic breast cancer," he added.
Results of three phase III studies - E2100, AVADO and RIBBON-1 - have shown the clinical benefit of adding bevacizumab to chemotherapy as a first-line metastatic breast cancer treatment. Brufsky and colleagues designed RIBBON-2 to evaluate the effectiveness and safety of adding bevacizumab to chemotherapy as a second-line treatment of metastatic breast cancer.
The study included 684 patients in 19 countries at 211 sites. Patients were eligible if they met the following criteria: they had one prior chemotherapy treatment for metastatic breast cancer, they were able to perform most daily activities, they had no central nervous system metastases, and their tumors did not over produce the HER2 protein.
The primary endpoint was progression-free survival; secondary endpoints included overall survival, overall response rate, duration of response and safety. Researchers randomly assigned patients to chemotherapy plus bevacizumab or chemotherapy plus placebo.
The results were predictable, Brufsky said. Adding bevacizumab to various chemotherapy regimens as a second-line metastatic breast cancer treatment significantly improved progression-free survival.
"The fact that bevacizumab has a benefit in first- and second-line treatment really begs the question: Should we be giving this drug to someone through the entire course of metastatic disease?" he said.
To address this question, Brufsky and colleagues are considering conducting a long-term clinical trial that compares bevacizumab or no bevacizumab treatment in women with metastatic breast cancer.
Br J Cancer. 2008 Nov 18;99(10):1564-71. Epub 2008 Oct 21.
Preoperative bevacizumab combined with letrozole and chemotherapy in locally advanced ER- and/or PgR-positive breast cancer: clinical and biological activity.
Torrisi R,
Bagnardi V,
Cardillo A,
Bertolini F,
Scarano E,
Orlando L,
Mancuso P,
Luini A,
Calleri A,
Viale G,
Goldhirsch A,
Colleoni M.
Department of Medicine, Research Unit of Medical Senology, European Institute of Oncology Milan, Milan, Italy.
rosalba.torrisi@ieo.it
The antiangiogenic agent bevacizumab showed synergistic effects when combined with chemotherapy in advanced breast cancer.
We presently investigated the activity of bevacizumab in combination with chemotherapy, including capecitabine and vinorelbine, and endocrine therapy, including letrozole (+triptorelin in premenopausal women), as primary therapy for patients with ER and/or PgR > or =10% T2-T4a-c, N0-N2, M0 breast cancer. Biological end point included the proliferative activity (Ki67), whereas clinical end points were clinical response rate, pathological complete response (pCR) and tolerability. Circulating endothelial cells (CECs) and their progenitors, as surrogate markers of antiangiogenic activity, were measured at baseline and at surgery.Thirty-six women are evaluable. A clinical response rate of 86% (95% CI, 70-95) and no pCR were observed; Ki67 was significantly decreased by 71% (interquartile range, -82%, -62%). Toxicity was manageable: two grade 3 hypertension, four grade 3 deep venous thrombosis and no grade >2 proteinuria were observed.
Treatment significantly decreased the percentage of viable CECs and prevented the chemotherapy-induced mobilisation of circulating progenitors. Basal circulating progenitors were positively associated with clinical response. In conclusion,
bevacizumab is feasible and active in association with primary chemoendocrine therapy for ER-positive tumours in terms of proliferation inhibition, clinical response and antiangiogenic activity.
PMID: 18941458 [PubMed - indexed for MEDLINE]
Rev Recent Clin Trials. 2009 Sep;4(3):163-7.
The use of bevacizumab and trastuzumab beyond tumor progression: a new avenue in cancer treatment?
Meriggi F,
Abeni C,
Di Biasi B,
Zaniboni A.
Oncology Department, Fondazione Poliambulanza, Brescia, Italy.
The use of the Monoclonal Antibodies (MoAbs) Bevacizumab (B) and Trastuzumab (T) beyond clinical progression in colorectal and breast cancer treatment is among the hottest topics in today's clinical oncology. Both
observational and prospective studies, based on a sound preclinical basis, seem to support the notion that, simply replacing the cytotoxic drugs combined with the two MoAbs would provide an additional clinical benefit without stopping the biological agent. The aim of this review is to provide a critical analysis of the available clinical data, while waiting for the confirmatory prospective clinical trials still ongoing.
The strength and the weakness of this innovative strategy, as well as the associated expense and toxicity issues will be discussed.
PMID: 20028327 [PubMed - in process]
BioDrugs. 2009;23(5):289-304. doi: 10.2165/11317600-000000000-00000.
Monoclonal antibodies targeting vascular endothelial growth factor: current status and future challenges in cancer therapy.
Hsu JY,
Wakelee HA.
Department of Medicine, Division of Oncology, Stanford Cancer Center, Stanford University, Stanford, California 94305-5826, USA.
The use of monoclonal antibodies targeting the vascular endothelial growth factor (VEGF) pathway has been a significant addition to cancer therapy. One of the VEGF family members, VEGF-A (commonly referred to as VEGF), has been demonstrated to be important in angiogenesis. Although the mechanism of action of these antibodies is still under study, the anti-VEGF antibody bevacizumab has been approved for treatment of various solid cancers including colorectal, lung, and breast cancers as well as glioblastoma and renal cell carcinoma.
Addition of bevacizumab to chemotherapy as adjuvant therapy in colorectal cancer did not improve disease-free survival. Bevacizumab is being tested in other clinical settings such as adjuvant therapy, maintenance therapy, and in combination with both chemotherapy and other targeted agents such as the epidermal growth factor receptor kinase inhibitor erlotinib. In addition to bevacizumab, other antibody-based therapies targeting the VEGF pathway are being tested. Ramucirumab and IMC-18F1 are monoclonal antibodies that target the VEGF receptors VEGFR-2 and VEGFR-1, respectively. Aflibercept (VEGF-Trap), a peptide-antibody fusion targeting VEGF ligand, is being tested in clinical trials. Much research is focused on identifying biomarkers to predict which patients will benefit from anti-VEGF therapy. Recent results suggest that VEGF single nucleotide polymorphisms may be predictive of patient response to bevacizumab. Improved imaging modalities such as dynamic contrast-enhanced MRI (DCE-MRI) can better characterize the efficacy of anti-angiogenic agents. As anti-VEGF treatments such as bevacizumab have been integrated into the treatment of many different types of cancers, the development of bevacizumab-resistant tumors has become more common.
Recent studies show that targeting other angiogenesis signaling pathways such as platelet-derived growth factor-C (PDGF-C), Bombina variagata peptide 8 (Bv8, also known as prokineticin-2), and VEGFR-3 may lead to enhanced response in anti-VEGF resistant tumors. In the future, tailored treatments consisting of combinations of chemotherapy, other targeted therapies, and anti-angiogenesis agents will hopefully result in better patient outcomes.
PMID: 19754219 [PubMed - indexed for MEDLINE]
Clin Cancer Res. 2010 Jan 1;16(1):269-78. Epub 2009 Dec 22.
Bevacizumab safety in patients with central nervous system metastases.
Besse B,
Lasserre SF,
Compton P,
Huang J,
Augustus S,
Rohr UP.
Institut Gustave Roussy, Villejuif, France.
benjamin.besse@igr.fr
PURPOSE: Patients with central nervous system (CNS) metastases were excluded from bevacizumab trials following a case of fatal cerebral hemorrhage in a patient with hepatocellular carcinoma in 1997. Safety information for bevacizumab-treated patients with CNS metastases was reviewed to determine whether general exclusion of these patients from bevacizumab treatment is still justified. EXPERIMENTAL DESIGN: A retrospective exploratory analysis was conducted using datasets from 13 randomized controlled phase II/III trials (dataset A), two open-label single-arm safety trials (dataset B), and two prospective studies including patients with treated CNS metastases (dataset C). In datasets A and B, known CNS metastasis was an exclusion criterion; patients with CNS metastasis had unrecognized CNS metastases at study entry or developed them during the trial. All reported cerebral hemorrhage grades in patients with CNS metastases were quantified. RESULTS: In dataset A, occult brain metastases were identified in 187 of 8,443 patients (91 in bevacizumab arms and 96 in non-bevacizumab arms). Three bevacizumab-treated patients (3.3%) developed grade 4 cerebral hemorrhage, whereas one control-arm patient (1.0%) developed grade 5 cerebral hemorrhage. In dataset B, 321 of 4,382 patients had initially occult CNS metastases, in whom two grade 1 and one grade 3 cerebral hemorrhage (0.9%) were reported. In 131 patients with treated CNS metastases in dataset C, one bevacizumab-treated patient (0.8%) developed grade 2 cerebral hemorrhage. CONCLUSIONS:
In this selected population, patients with CNS metastases are at similar risk of developing cerebral hemorrhage, independent of bevacizumab therapy. Consequently, such patients with CNS metastases from advanced/metastatic breast cancer, non-small cell lung carcinoma, and renal and colorectal cancer should not be generally excluded from bevacizumab therapy or clinical trials.
PMID: 20028762 [PubMed - in process]
German researchers detail how metastatic cancer takes root in the brain
By Greg Freiherr | January 11, 2010
LINK
As many as one in four cancer patients develop metastatic cancers of the brain. Existing therapies seldom do more than slow the disease. Adding to the urgency to find a way to prevent brain metastasis is the increasing number of such cases.
"Improvements in the treatment of malignancy have enhanced survival time," said Dr. Frank Winkler, who leads the Neurooncology Research Group at the Ludwig-Maximilians-Universität (LMU) Neurological Clinic in Munich. "But this also means that more patients are at risk of developing brain metastases."
In the hope of finding ways to stop this process, Winkler and colleagues at LMU and neighboring Max Planck Institute for Neurobiology have defined, in animals, the steps that lead some tumor cells to metastasize. Reporting days before Christmas in the online version of
Nature Medicine, Winkler and colleagues detailed the process of brain metastasis. To do so they used two-photon microscopy to look deeply into animal tissues and visualize at high resolution structures that lay hundreds of micrometers below the surface of the living brain.
The metastatic process begins, they found, when circulating tumor cells are trapped in a network of blood vessels. The cells then pass through tiny gaps between cells in the vessel wall, escaping into the surrounding brain tissue, yet sticking to the outer surface of the vessel. Here is where the process begins in earnest, as between four and fifty cells form micrometastases that ultimately fuse, triggering the growth of new blood vessels to feed the mass.
Interrupting any one of the steps will stop metastatic cancer in its tracks, according to Winkler. His team is now looking for ways to do exactly that. One may already be at hand. In their animal research, the team detailed how the anticancer drug Avastin can suppress the emergence of metastases by blocking the formation of new blood vessels. In the absence of such angiogenesis, even cells that had attached to the outer vessel wall and proliferated strongly at first eventually died, he says.
"We now want to test other types of cancer drugs for their effects on the single steps of metastasis formation," Winkler said. "It may be possible to discover new substances that allow us to treat existing metastases effectively, or even prevent them from developing at all."
Oncology. 2010 Jan 11;77(6):358-365. [Epub ahead of print]
Safety, Tolerability and Biological Effects of Long-Term Metronomic Administration of Non-Cytotoxic Anti-Angiogenic Agents.
Noberasco C,
Spitaleri G,
Mancuso P,
Zorzino L,
Radice D,
Milani A,
Rocca A,
Bertolini F,
Sandri MT,
Curigliano G,
de Pas T,
Jemos C,
Omodeo Salè E,
Boselli S,
de Braud F.
Clinical Pharmacology and New Drugs Development Unit, Department of Medicine, European Institute of Oncology, Milan, Italy.
Background:
alpha-Interferon, thalidomide and celecoxib inhibit tumour angiogenesis by differing mechanisms. Patients and Methods: In a randomized phase II trial to assess tolerability and safety,
we assigned patients with advanced slow-growing solid tumours to 1 of 6 two- or three-drug combinations: alpha-interferon 0.5 million IU b.i.d., thalidomide (100 mg b.i.d. reduced to 100 mg daily), or celecoxib (400 mg daily reduced to 200 mg). Circulating endothelial cells and progenitors (CECs, CEPs) and vascular endothelial growth factor were also studied. Results: From January 2002 to September 2005, 62 patients were enrolled. Four months after initiating treatment, 3 (4%) had partial response, 40 (64%) had stable disease and 19 (30%) had disease progression. Median duration of clinical benefit (partial response/stable disease) was 11.3 months.
Patients receiving a third drug had significantly less stable disease plus partial response (chi(2) test, p = 0.002) than those receiving two drugs. The treatments were generally well tolerated, but neurotoxicity (G3 lethargy) occurred in 6 patients. Baseline CEPs were lower (p = 0.004) in patients with clinical benefit at 6 months than those without benefit. After 2 months of treatment CECs were lower than at baseline (p = 0.018) in patients without clinical benefit, and CEPs were higher than at baseline (p = 0.003) in patients with benefit. Conclusions:
In pretreated patients with advanced slow-growing solid tumours, long-term metronomic administration of two-drug combinations of alpha-interferon, thalidomide or celecoxib was well tolerated and had antitumour activity. Low baseline CEPs in patients with subsequent clinical benefit suggest that CEC count may identify patients likely to benefit from long-term metronomic anti-angiogenic treatment. Copyright © 2010 S. Karger AG, Basel.
PMID: 20068365 [PubMed - as supplied by publisher]
Thalidomide fail or dosage fail?
Cancer Invest. 2010 Mar 8. [Epub ahead of print]
Phase II Study of Capecitabine in Combination With Thalidomide in Patients With Metastatic Breast Cancer.
Burris HA,
Jones SF,
Shipley D,
Meluch AA,
Greco FA,
Barton JH,
Yardley DA,
Hainsworth JD.
Sarah Cannon Research Institute, Nashville, Tennessee, USA,1.
ABSTRACT We examined the toxicity/efficacy of capecitabine with thalidomide, administered over 21-day cycles, in 24 previously treated metastatic breast cancer (MBC) patients. This regimen was poorly tolerated: grade 3/4 neutropenia (13%); grade 3 nausea (22%), vomiting (17%), and diarrhea (13%); and grade 2/3 hand-foot syndrome (38%). In addition, the response rate was lower than expected: partial response (13%), stable disease (17%), and progressive disease at first evaluation (35%). The median time to progression and overall survival were 2.7 and 11.0 months, respectively.
These results do not support further investigation of thalidomide for MBC. The role of angiogenesis inhibition in breast cancer treatment should continue to be defined using more efficacious and specific inhibitors.
PMID: 20210519 [PubMed - as supplied by publisher]
PCAAC: Prostate cancer antiangiogenic cocktail (2002, Liebowitz):
http://compassionateoncology.org/pdfs/cocktail9602.pdf
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The use of multi-target therapeutic strategies, in particular inhibitors of angiogenesis with metronomic schedules of cytotoxic agents, is to achieve long-term control of cancer, or induce a dormant state in residual areas of tumor, without unacceptable toxic effects. It appears that survival time depends more on merely containing cancer than on actually shrinking it. The goal of chemotherapy has always been to shrink cancer. We must realistically appreciate that we are not going to be able to cure metastatic prostate cancer. We can, however, achieve very long-term control.
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patients are being treated with GM-CSF, interferon, Proscar, Celebrex, Herceptin, thalidomide, low-dose Cytoxan and Lovenox (or Coumadin).
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2008 Liebowitz AAC update:
http://compassionateoncology.org/pdf...tail082508.pdf
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Over the years, various ingredients in my AAC would appear, but if I was not impressed with their ability to help control prostate cancer (CaP), their inclusion in the AAC was shortlived. However, a few medications have enjoyed charter member status. The two most effective drugs are clearly Leukine (GM-CSF) and the combination of thalidomide/Revlimid. For most patients, insurance coverage permitting, we use thalidomide 50 mg, alternating with Revlimid 5 mg. We never use both drugs the same day, nor do we ever use more than one total capsule on
any day.
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Unlike thalidomide, Revlimid does not cause drowsiness, peripheral neuropathy symptoms, constipation, or slow heart rates. Revlimid may lower a patient’s platelet count. Platelets help your blood to clot. We monitor blood counts carefully and frequently whenever one of our patients is being treated with Revlimid.
As of August 2008, I believe (opinion) that 95% of the beneficial results from AAC are due to Leukine and thalidomide/Revlimid.
Some of the minor AAC players that may help our patients include Proscar, Avodart, Celebrex (but only 200 mg once a day to reduce the risk of cardiovascular
complications), and statins (like Crestor) to lower cholesterol and reduce the risk of dying from cardiovascular events. A number of studies have found that men on statins who develop prostate cancer have a lower risk of developing advanced or
metastatic cancer, as well as a lower risk of dying from metastatic prostate cancer. Still other minor AAC players include anticoagulation with low-molecular weight heparin (not warfarin/Coumadin), mini-mini-dose alpha interferon, and perhaps vitamin D. Avastin is also possibly a major significant player and we try to use it in certain settings, but I do not believe it is anywhere near as effective as Leukine and thalidomide/Revlimid. We also may use a metronomic schedule of oral cyclophosphamide (Cytoxan) in tiny mini-doses. At times, we may add another category of drugs called targeted therapy. Currently, our targeted drug of choice is Nexavar, but previously we tried Iressa, Tarceva, Sutent, and Gleevec.
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One of the nicest things about this regimen is that both of these medications enhance the immune system. Many cancer patients are concerned that chemotherapy can adversely affect their immune system; with Leukine and thalidomide, the opposite occurs.
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Eur J Cancer. 2000 Jun;36(10):1248-57.
'Accidental' anti-angiogenic drugs. anti-oncogene directed signal transduction inhibitors and conventional chemotherapeutic agents as examples.
Kerbel RS,
Viloria-Petit A,
Klement G,
Rak J.
Sunnybrook and Women's College Health Sciences Centre, Division of Cancer Biology Research, S-218, 2075 Bayview Avenue, Ontario M4N 3M5, Toronto, Canada.
kerbel@srcl.sunnybrook.utoronto.ca
A number of drugs currently being tested in clinical trials as possible angiogenesis inhibitors were not originally developed with the intention of suppressing tumour angiogenesis. Thalidomide and interferon alpha are obvious examples of such drugs. This list of 'accidental' angiogenesis inhibitors may include established agents such as conventional cytotoxic chemotherapeutic drugs as well as the new generation of anticancer drugs known as anti-oncoprotein signal transduction inhibitors. With respect to the former, the potential of such drugs to inhibit angiogenesis could be the result of their ability to cause collateral damaging effects on cycling endothelial cells found in newly formed blood vessels, or inhibiting other vital endothelial cell functions necessary for angiogenesis. The
antitumour vascular side-effects of chemotherapy may be optimised by administering such drugs continuously on a more frequent (e.g. weekly or even daily) basis at levels well below the maximum tolerated dose (MTD), especially when this is done in combination with newly developed anti-angiogenic drugs such as vascular endothelial cell growth factor (VEGF) receptor blocking antibodies. This strategy may minimise or delay the problems of host toxicity and acquired drug resistance. The possibility of
anti-angiogenic effects mediated by signal transduction inhibitors such as ras farnesyltransferase inhibitors (ras FTI's), or drugs which block receptor tyrosine kinases (e.g. ErbB2/neu) such as Herceptin, may be the consequence of such oncogenes inducing or upregulating various pro-angiogenic molecules such as VEGF (vascular endothelial cell growth factor) in tumour cells. Hence, treatment of tumour cells with such drugs can lead to downregulation of tumour cell-associated VEGF expression and this can contribute to an anti-angiogenic effect of the drug in vivo. In addition, some of these drugs may also affect certain 'activated' endothelial cell functions directly so as to block angiogenesis. An awareness of the potential of such conventional or experimental anticancer drugs to affect tumour growth through blockade or suppression of angiogenesis has implications for how anticancer drugs may be used clinically, either alone, or in combination with other drugs to optimally treat cancer.
PMID: 10882863 [PubMed - indexed for MEDLINE]
Cancer Res. 2009 Jul 15;69(14):5893-900. Epub 2009 Jun 30.
Acetyl-11-keto-beta-boswellic acid inhibits prostate tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis.
Pang X,
Yi Z,
Zhang X,
Sung B,
Qu W,
Lian X,
Aggarwal BB,
Liu M.
Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
The role of angiogenesis in tumor growth and metastasis is well established. Identification of a small molecule that blocks tumor angiogenesis and is safe and affordable has been a challenge in drug development. In this study, we showed that
acetyl-11-keto-beta-boswellic acid (AKBA), an active component from an Ayurvedic medicinal plant (Boswellia serrata), could strongly inhibit tumor angiogenesis. AKBA suppressed tumor growth in the human prostate tumor xenograft mice treated daily (10 mg/kg AKBA) after solid tumors reached approximately 100 mm(3) (n = 5). The inhibitory effect of AKBA on tumor growth was well correlated with suppression of angiogenesis. When examined for the molecular mechanism, we found that AKBA significantly inhibited blood vessel formation in the Matrigel plug assay in mice and effectively suppressed vascular endothelial growth factor (VEGF)-induced microvessel sprouting in rat aortic ring assay ex vivo. Furthermore,
AKBA inhibited VEGF-induced cell proliferation, chemotactic motility, and the formation of capillary-like structures from primary cultured human umbilical vascular endothelial cells in a dose-dependent manner. Western blot analysis and in vitro kinase assay revealed that AKBA suppressed VEGF-induced phosphorylation of VEGF receptor 2 (VEGFR2) kinase (KDR/Flk-1) with IC(50) of 1.68 micromol/L. Specifically, AKBA suppressed the downstream protein kinases of VEGFR2, including Src family kinase, focal adhesion kinase, extracellular signal-related kinase, AKT, mammalian target of rapamycin, and ribosomal protein S6 kinase. Our findings suggest that AKBA potently inhibits human prostate tumor growth through inhibition of angiogenesis induced by VEGFR2 signaling pathways.
PMID: 19567671 [PubMed - indexed for MEDLINE]
Cancer Res. 2008 Mar 15;68(6):2043-50.
Silibinin inhibits colorectal cancer growth by inhibiting tumor cell proliferation and angiogenesis.
Singh RP,
Gu M,
Agarwal R.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, CO 80262, USA.
Herein, for the first time, we investigated in vivo efficacy and associated molecular biomarkers and mechanisms of a chemopreventive agent, silibinin, against human colorectal carcinoma (CRC) HT29 xenograft growth.
Nude mice were implanted with HT29 cells and fed with vehicle (carboxymethyl cellulose or phosphatidylcholine) or 200 mg/kg/d dose of silibinin or 100 and 200 mg/kg/d doses of silybin-phytosome (5 days per week) for 32 days. Silibinin inhibited tumor growth that accounted for 48% (P = 0.002) decrease in tumor volume and 42% (P = 0.012) decrease in tumor weight at the end of the experiment without any adverse health effect. A stronger antitumor efficacy was observed with silybin-phytosome preparation. Silibinin decreased proliferation index by 40% (P < 0.001), increased apoptotic index by approximately 2-fold (P = 0.001), and reduced microvessel density by 36% (P = 0.001) in tumors. Antiproliferative and proapoptotic effects of silibinin were associated with down-regulation of extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt phosphorylation as well as cyclin D1 expression.
Antiangiogenic effect of silibinin was coupled with a strong decrease in inducible nitric oxide synthase (NOS) and NOS3, cyclooxygenase-1 (COX-1) and COX-2, and hypoxia-inducing factor-1 alpha (HIF-1 alpha) and vascular endothelial growth factor (VEGF). These findings suggest in vivo antitumor efficacy of silibinin against CRC involving its antiproliferative, proapoptotic, and antiangiogenic activities.
The inhibition of ERK1/2 and Akt signaling may account for antiproliferative and proapoptotic effects, whereas down-regulation of NOS, COX, HIF-1 alpha, and VEGF expression could lead to antiangiogenic effect of silibinin against CRC. Overall, potential use of silibinin against human CRC could be suggested.
PMID: 18339887 [PubMed - indexed for MEDLINE]
Suppression of angiogenesis, tumor growth,and wound healing by resveratrol, a natural compound in red wine and grapes
The FASEB Journal express article 10.1096/fj.01-0028fje. Published online June 8, 2001.
Ebba Bråkenhielm,* Renhai Cao,* and Yihai Cao
The first two authors contributed equally to this work.
Corresponding author: Yihai Cao, M.D., Ph.D., Laboratory of Angiogenesis Research,
Microbiology and Tumor Biology Center, Karolinska Institute, S-171 77 Stockholm, Sweden. Email:
yihai.cao@mtc.ki.se
FREE PDF
ABSTRACT
Resveratrol (3,5,4'-trihydroxystilbene) is a natural compound found in several plants, including grapes, peanuts, and pines, and in their related products. Red wine is probably the most frequently consumed drink that is enriched in resveratrol.
We investigated whether drinking resveratrol could suppress angiogenesis, a process of blood vessel growth involved in initiation, development, and progression of many diseases, including cancer, metastasis, and diabetic retinopathy. We found that resveratrol suppresses the growth of new blood vessels in animals.
It
directly inhibits capillary endothelial cell growth. It blocks both VEGF- and FGF-receptor mediated angiogenic responses. In addition, resveratrol inhibits the phosphorylation of mitogenactivated kinase isoforms (MAPKp44/MAPKp42) induced by fibroblast growth factor-2 in proliferating endothelial cells in a dose-dependent manner. Oral administration of resveratrol significantly inhibits the growth of a murine fibrosarcoma in mice, and it significantly delays angiogenesis-dependent wound healing in mice. Our findings suggest that ingestion of resveratrol-enriched food could be beneficial for the prevention of cancer. However, its antiangiogenic effect could delay wound healing and possibly other angiogenesis-dependent processes under physiological conditions.
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At a concentration of 1 μM, resveratrol significantly inhibited the VEGF-induced
PAE/VEGFR-2 endothelial cell migration (Fig. 1F). These data demonstrate that resveratrol inhibits both FGF- and VEGF-receptor-mediated endothelial cell growth and chemotaxis.
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Inhibition of FGF- and VEGF-induced angiogenesisTo further investigate whether resveratrol could suppress angiogenesis in mammals, we prepared a drinking solution for mice, containing 0.4 μg/ml resveratrol in 1% ethano,l which was equivalent to the amount of resveratrol found in approximately three glasses of red wine
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Our present study is consistent with previous reports that resveratrol inhibits both tumor formation and the growth of tumor implants in animals (8). The growth of primary tumors and metastases depends on the degree of tumor neovascularization (9–11). This study provides compelling evidence that suppression of angiogenesis could be at least one of the mechanisms of the antitumor effect of resveratrol. Consumption of resveratrol could be beneficial in the prevention of angiogenesis-dependent diseases. However, we should emphasize that the antiangiogenic effect of resveratrol could be harmful in situations such as wound healing.
Recent studies suggest that antiangiogenic therapy has to be delivered for long-term periods in order to arrest a tumor at its dormant stage (9, 19). In clinical settings, most angiogenesis inhibitors have to be delivered to cancer patients by systemic injections for several years. Thus, there would be great advantages if oral angiogenesis inhibitors were available. Resveratrol, as a small molecule and an oral angiogenesis inhibitor found in natural food products, could well fulfill the criteria of long-term antiangiogenic therapy without injections.
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Recent studies suggest that antiangiogenesis therapy in combination with other existing therapies, including chemotherapy and radiotherapy, produces synergistic efficacy against disease conditions (23). For example, angiostatin and ionizing radiation synergistically suppress tumor growth in animals.
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Taken together with our other recent finding that EGCG in green tea is an angiogenesis inhibitor (4), consumption of various plant products containing polyphenol-based compounds and adequate amounts of red wine may be beneficial in the prevention of cancer. Paradoxically, they might delay physiological processes in which angiogenesis is required.
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Carcinogenesis. 2004 Nov;25(11):2115-23. Epub 2004 Aug 5.
Anti-angiogenic activity of inositol hexaphosphate (IP6).
Vucenik I,
Passaniti A,
Vitolo MI,
Tantivejkul K,
Eggleton P,
Shamsuddin AM.
Department of Medical and Research Technology, University of Maryland School of Medicine, Baltimore, MD, USA.
A significant anticancer activity of the naturally occurring carbohydrate inositol hexaphosphate (IP(6)) has been reported against numerous cancer models. Since tumors require angiogenesis for growth and metastasis, we hypothesize that IP(6) reduces tumor growth by inhibiting angiogenesis. Because angiogenesis depends on the interaction between endothelial and tumor cells, we investigated the effect of IP(6) on both.
IP(6) inhibited the proliferation and induced the differentiation of endothelial cells in vitro; the growth of bovine aortic endothelial cells (BAECs) evaluated by MTT proliferation assay was inhibited in a dose-dependent manner (IC(50) = 0.74 mM).
The combination of IP(6) and vasostatin, a calreticulin fragment with anti-angiogenic activity, was synergistically superior in growth inhibition than either compound. IP(6) inhibited human umbilical vein endothelial cell (HUVEC) tube formation (in vitro capillary differentiation) on a reconstituted extracellular matrix, Matrigel, and disrupted pre-formed tubes. IP(6) significantly reduced basic fibroblast growth factor (bFGF)-induced vessel formation (P < 0.01) in vivo in Matrigel plug assay.
Exposure of HepG2, a human hepatoma cell line, to IP(6) for 8 h, resulted in a dose-dependent decrease in the mRNA levels of vascular endothelial growth factor (VEGF), as assessed by RT-PCR. IP(6) treatment of HepG2 cells for 24 h also significantly reduced the VEGF protein levels in conditioned medium, in a concentration-dependent manner (P = 0.012). Thus, IP(6) has an inhibitory effect on induced angiogenesis.
PMID: 15297368 [PubMed - indexed for MEDLINE]
Cancer Res. 2007 Apr 15;67(8):3560-4.
Anticancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors.
Folkins C,
Man S,
Xu P,
Shaked Y,
Hicklin DJ,
Kerbel RS.
Department of Molecular and Cellular Biology Research, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Avenue, Toronto, Ontario, Canada.
Vascular endothelial cells have been identified as a critical component of the neural stem cell niche, raising the possibility that brain tumor stem-like cells (TSLC) may also rely on signaling interactions with nearby tumor vasculature to maintain their stem-like state. The disruption of such a TSLC vascular niche by an antiangiogenic therapy could result in loss of stemness characteristics associated with intrinsic drug resistance and, thus, preferentially sensitize TSLC to the effects of chemotherapy. Considering these possibilities,
we investigated the impact of antiangiogenic anticancer therapy on the TSLC fraction of glioma tumors. Athymic nude mice bearing s.c. tumor xenografts of the C6 rat glioma cell line were treated with either a targeted antiangiogenic agent, antiangiogenic schedules of low-dose metronomic chemotherapy, combination therapies of antiangiogenic agents and chemotherapy, or, for the purpose of comparison, a conventional cytotoxic schedule of maximum tolerated dose chemotherapy using cyclophosphamide.
Targeted antiangiogenic therapy or cytotoxic chemotherapy did not reduce the fraction of tumor sphere-forming units (SFU) in the tumor, whereas all treatment groups that combined both antiangiogenic and cytotoxic drug effects caused a significant reduction in SFU. This work highlights the possibility that selective eradication of TSLC may be achieved by targeting the tumor microenvironment (and potentially a supportive TSLC niche) rather than the TSLC directly. Furthermore, this work suggests a possible novel effect of antiangiogenic therapy, namely, as a chemosensitizer of TSLC, and thus represents a possible new mechanism to explain the ability of antiangiogenic therapy to enhance the efficacy of chemotherapy.
PMID: 17440065 [PubMed - indexed for MEDLINE]
Br J Cancer. 2010 Jan 5. [Epub ahead of print]
Combination therapy: intermittent sorafenib with bevacizumab yields activity and decreased toxicity.
Lee JM,
Sarosy GA,
Annunziata CM,
Azad N,
Minasian L,
Kotz H,
Squires J,
Houston N,
Kohn EC.
Medical Ovarian Cancer Team, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Background:
We previously reported preliminary results of our phase I study of continuous daily sorafenib with bevacizumab every other week for solid tumours. Toxicity was moderate, leading to additional dose levels (DL) testing intermittent sorafenib dosing.
Methods: Seventeen patients with advanced solid tumours were treated on three additional DLs testing sorafenib days 1-5 per week. Dose level 4 was sorafenib 200 mg twice daily (b.i.d.) and bevacizumab 5 mg kg(-1). DL5 alternated between bevacizumab 10 mg kg(-1)-sorafenib 200 mg b.i.d. (A) and sorafenib 400 mg b.i.d. with bevacizumab 5 mg kg(-1) (B). Outcome and toxicity data from 19 epithelial ovarian cancer (EOC) patients from DL 1-5 were analysed.
Results: Fewer patients required sorafenib dose reduction with the intermittent schedule (41 vs 74% daily, P=0.01). Hand-foot skin reaction (HFSR) remained the primary cause of dose reduction (n=5). Partial responses (12%) or disease stabilisation >/=4 months (53%; median 6 (4-26)) occurred in most patients on the intermittent schedule. Partial response occurred in 47% EOC patients treated in pooled analysis of duration 4-37 months.
Conclusion:
Intermittent sorafenib dosing with bevacizumab has promising clinical activity and less sorafenib dose reduction and side effects, but does not ameliorate HFSR. We are conducting a phase II clinical trial with intermittent sorafenib and bevacizumab in patients with EOC.British Journal of Cancer advance online publication, 5 January 2010; doi:10.1038/sj.bjc.6605514
www.bjcancer.com.
PMID: 20051952 [PubMed - as supplied by publisher]
Cancer Chemother Pharmacol. 2010 Jan 28. [Epub ahead of print]
Phase 1 study of the investigational, oral angiogenesis inhibitor motesanib in Japanese patients with advanced solid tumors.
Fujisaka Y,
Yamada Y,
Yamamoto N,
Shimizu T,
Fujiwara Y,
Yamada K,
Tamura T,
Watanabe H,
Sun YN,
Bass MB,
Seki M.
Division of Internal Medicine, National Cancer Center Hospital, 5-1-1, Tsukiji Chuo-Ku, Tokyo, 104-0045, Japan,
yfujisaka@gmail.com.
PURPOSE: The aim of this study was to investigate the safety and pharmacokinetics of motesanib (AMG 706), a small-molecule antagonist of vascular endothelial growth factor receptors 1, 2, and 3, platelet-derived growth factor receptor, and c-Kit in Japanese patients with advanced solid tumors. METHODS: Patients were administered motesanib orally once daily (QD) at doses of 50, 100, and 125 mg QD. The total study duration for each patient consisted of three cycles of 28 days per cycle. The primary endpoints were the incidence of dose-limiting toxicities (DLTs), estimation of the maximum tolerated dose (MTD), and assessment of pharmacokinetic parameters of motesanib. RESULTS: Fifteen patients were enrolled and received motesanib.
No DLTs were observed and, therefore, the MTD was not reached. Motesanib had acceptable toxicity at doses up to 125 mg QD. The pharmacokinetics of motesanib appears to be dose proportional.
No objective responses per RECIST were observed. However, all 15 patients achieved stable disease, and five patients had durable (>24 weeks) stable disease. CONCLUSIONS: The results of this study demonstrate that motesanib is tolerable in Japanese patients at doses up to 125 mg QD.
PMID: 20107802 [PubMed - as supplied by publisher]
Clin Cancer Res. 2008 May 15;14(10):3070-6.
Tamoxifen and aromatase inhibitors differentially affect vascular endothelial growth factor and endostatin levels in women with breast cancer.
Holmes CE,
Huang JC,
Pace TR,
Howard AB,
Muss HB.
Department of Medicine, University of Vermont, Burlington, Vermont, USA.
ceholmes@uvm.edu
PURPOSE: Circulating and cellular proangiogenic and antiangiogenic proteins such as vascular endothelial growth factor (VEGF) and endostatin contribute to the local angiogenic balance. We explored the effects of tamoxifen and aromatase inhibitors on concentrations of VEGF and endostatin in plasma, serum, and platelet releasate (induced by platelet activation). EXPERIMENTAL DESIGN: VEGF and endostatin concentrations were measured with a quantitative immunoassay before and after 1 to 5 weeks of treatment in 30 women with breast cancer treated with either tamoxifen (n = 14) or aromatase inhibitors (n = 16). Platelet activation was induced by a thrombin receptor agonist. RESULTS:
Tamoxifen therapy resulted in an increase in platelet releasate concentrations of VEGF (P = 0.01) but no change in plasma VEGF. In contrast, aromatase inhibitor therapy did not affect serum, plasma, or platelet releasate VEGF. In univariate analysis, aspirin use attenuated the tamoxifen-associated increase in VEGF in the platelet releasate and decreased serum levels of VEGF (P = 0.03). Aromatase inhibitor therapy resulted in a decrease in serum endostatin concentrations (P = 0.04), whereas plasma concentrations of endostatin tended to be higher during treatment with aromatase inhibitors (P = 0.06). Tamoxifen therapy resulted in no change in serum or plasma endostatin concentrations. Platelet releasate concentrations of endostatin did not change with either treatment. Interindividual variability was noted among both aromatase inhibitor--and tamoxifen-treated patients. CONCLUSIONS:
Tamoxifen and aromatase inhibitor therapy affect VEGF and endostatin levels and likely contribute to the angiogenic balance in breast cancer patients. Aspirin decreased the proangiogenic effects of tamoxifen, suggesting that antiplatelet and/or antiangiogenic therapy might improve the effectiveness of tamoxifen in women with breast cancer.
PMID: 18483373 [PubMed - indexed for MEDLINE]
Re: Antiangiogenic agents
Linear Mode
