Investigation of Novel Fumagillin Analogues as Angiogenesis Inhibitors.

Pyun, Hyung‐Jung; Fardis, Maria; Tario, James; Yang, Chui‐Ping; Ruckman, Judy; Henninger, Dwight; Jin, Haolun; Kim, Choung U.

doi:10.1002/chin.200417221

Cited by 3 publications

(3 citation statements)

References 1 publication

Supporting

Mentioning

Contrasting

Order By: Relevance

“…They have been tested only by in vitro assays, and to date, no clinical trials of these analogues have yet been conducted. 63,64 Since the angiogenic cascade is a multistep process, numerous assays have been developed to study potential angiogenic activity. Some analyze a single step in the pathway, whereas others test the angiogenic cascade as a whole.…”

Section: Screening Herbs For Antiangiogenic Activitymentioning

confidence: 99%

Targeting Angiogenesis With Integrative Cancer Therapies

2006

View full text Add to dashboard Cite

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.

show abstract

Section: Screening Herbs For Antiangiogenic Activitymentioning

confidence: 99%

Targeting Angiogenesis With Integrative Cancer Therapies

2006

View full text Add to dashboard Cite

show abstract

“…Compound 67 exhibited antiangiogenic effects similar to TNP-470 with the matrigel plug assay and rat corneal micropocket assay. Compound 67 is much more stable than TNP-470 against hydrolysis by epoxide hydrolase [87]. CKD-732 (68), IDR-803 (69), IDR-804 (70), and IDR-805 (71) are potent MetAP-2 inhibitors with improved solubility.…”

Section: Methionine Aminopeptidasementioning

confidence: 99%

Antiangiogenesis Drug Design: Multiple Pathways Targeting Tumor Vasculature

Zhong¹,

Bowen²

2006

CMC

View full text Add to dashboard Cite

The initiation, growth, and development of new blood vessels through angiogenesis are essential for tumor growth. Tumor masses require access to blood vessels for a sufficient supply of oxygen and nutrients to maintain growth and metastasis. Inhibiting tumor blood vessel formation as proposed by Judah Folkman in the early 1970s, therefore, offers promising therapeutic approaches for treating tumor afflicted patients. The blood vessel growth in normal tissues is regulated though a delicate and complex balance between the collective action of proangiogenic factors (e.g., vascular endothelial growth factor, VEGF) and the collective action of angiogenic inhibitors (e.g., thrombospondin-1). In pathological angiogenesis, the angiogenic switch is shifted toward the proangiogenic factors, and if the imbalance continues, irregular tumor vessel growth is the result. Despite intense research, the mechanism of the angiogenic switch is not fully understood. Many factors, however, have been shown to be involved in regulating the equilibrium between angiogenic stimulants and inhibitors. VEGFR tyrosine kinase, methionine aminopeptidase-2 (MetAP-2), p53, tubulin, cyclooxygenase-2 (COX-2), and matrix metalloproteinases (MMPs) all directly and/or indirectly influence the angiogenic switch. This review will describe some of the advances in inhibitor design and the mechanisms of action for the aforementioned factors (targets) involved in angiogenesis regulation. Our discussion reveals that a diaryl group separated by various connecting modules is one of the most common features for antiangiogenesis drug design. This idea has been a working pharmacophore hypothesis for our own antiangiogenic drug design endeavors over the years. The recent advances of combination therapy (angiogenesis inhibitors with other chemotherapy/radiation) are also discussed.

show abstract

“…Apart from its veterinary use, fumagillin belongs to a novel class of promising therapeutic agents to treat cancer and other human diseases. Indeed, fumagillin and its analogs are potently inhibit angiogenesis by directly inhibiting endothelial cell proliferation (Pyun et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Fumagillin, a new P‐glycoprotein‐interfering agent able to modulate moxidectin efflux in rat hepatocytes¹

Dupuy

Lespine

Sutra

et al. 2006

Vet Pharm & Therapeutics

View full text Add to dashboard Cite

We have tested the ability of two compounds licensed in veterinary medicine: fumagillin and diminazene diaceturate to increase intracellular moxidectin quantity in rat hepatocytes. These compounds significantly increased the quantity of 14C-moxidectin (expressed as area under the time curve concentrations) in cultured rat hepatocytes by 44% and 65% for diminazene and fumagillin treatments respectively. In addition, we have tested these drugs for their interference with P-glycoprotein (P-gp) function in porcine kidney epithelial cells transfected with murine mdr1a (Mdr1a-LLCPK1). We examined the intracellular accumulation of rhodamine 123 (Rho 123) as a functional test to evaluate the effects of these two drugs on P-gp activity. In this model, only fumagillin led to a marked intracellular accumulation of Rho 123. After transforming the data to express the results as a percentage of the accumulation in the presence of the P-gp inhibitor valspodar (VSP), the maximal Rho 123 accumulation was 47% of that with VSP for 100 microm fumagillin. The EC50, the concentration needed to determine 50% of the maximal effect was 34 microm. Fumagillin interacts with P-gp function and appears as a promising compound among registered drugs available, which may optimize the therapeutic use of macrocyclic lactones (MLs).

show abstract

Investigation of Novel Fumagillin Analogues as Angiogenesis Inhibitors.

Cited by 3 publications

References 1 publication

Targeting Angiogenesis With Integrative Cancer Therapies

Targeting Angiogenesis With Integrative Cancer Therapies

Antiangiogenesis Drug Design: Multiple Pathways Targeting Tumor Vasculature

Fumagillin, a new P‐glycoprotein‐interfering agent able to modulate moxidectin efflux in rat hepatocytes¹

Contact Info

Product

Resources

About

Investigation of Novel Fumagillin Analogues as Angiogenesis Inhibitors.

Cited by 3 publications

References 1 publication

Targeting Angiogenesis With Integrative Cancer Therapies

Targeting Angiogenesis With Integrative Cancer Therapies

Antiangiogenesis Drug Design: Multiple Pathways Targeting Tumor Vasculature

Fumagillin, a new P‐glycoprotein‐interfering agent able to modulate moxidectin efflux in rat hepatocytes1

Contact Info

Product

Resources

About

Fumagillin, a new P‐glycoprotein‐interfering agent able to modulate moxidectin efflux in rat hepatocytes¹