Hyaluronan, angiogenesis and malignant disease

Slevin, Mark; West, David C.; Kumar, Patricia; Rooney, Paul; Kumar, Shant

doi:10.1002/ijc.20059

Cited by 32 publications

(27 citation statements)

References 13 publications

(4 reference statements)

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“…HYALs are also implicated in the disruption of matrix vesicles required for bone mineralisation. The liberation of aggrecan G1 domain fragments and link protein from vesicles is dependent upon HYAL treatment [167]. These results are consistent with the hypothesis that aggrecan is resorbed prior to bone mineralisation, with the decrease in aggrecan content corresponding to the mineralising front [199].…”

Section: Hyal In Bonesupporting

confidence: 85%

Hyaluronan synthesis and degradation in cartilage and bone

Bastow

Byers

Golub

et al. 2007

Cell. Mol. Life Sci.

168

106

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Hyaluronan (HA) is a large but simple glycosaminoglycan composed of repeating D-glucuronic acid, beta1-3 linked to N-acetyl-D-glucosamine beta1-4, found in body fluids and tissues, in both intra- and extracellular compartments. Despite its structural simplicity, HA has diverse functions in skeletal biology. In development, HA-rich matrices facilitate migration and condensation of mesenchymal cells, and HA participates in joint cavity formation and longitudinal bone growth. In adult cartilage, HA binding to aggrecan immobilises aggrecan, retaining it at the high concentrations required for compressive resilience. HA also appears to regulate bone remodelling by controlling osteoclast, osteoblast and osteocyte behaviour. The functions of HA depend on its intrinsic properties, which in turn rely on the degree of polymerisation by HA synthases, depolymerisation by hyaluronidases, and interactions with HA-binding proteins. HA synthesis and degradation are closely regulated in skeletal tissues and aberrant synthetic or degradative activity causes disease. The role and regulation of HA synthesis and degradation in cartilage, bone and skeletal development is discussed.

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Section: Hyal In Bonesupporting

confidence: 85%

Hyaluronan synthesis and degradation in cartilage and bone

Bastow

Byers

Golub

et al. 2007

Cell. Mol. Life Sci.

168

106

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“…Follow-up of these 'non-responding' patients revealed that the patients were still alive at 623-629 days after commencement of treatment, with this survival period falling within the expected survival for responders as assessed by CEA [46] . While anecdotal, this discrepancy between a response as ascertained from CT versus CEA levels is consistent with the preclinical activity of the HA-Irinotecan investigational product, where previous studies have demonstrated that HA-chemotherapeutic drugs can reduce tumor neovascularization [38,45] . Similar observations of reduced CEA but delayed responses as detected with CT are often observed after treatment with antiangiogenic therapies [46][47][48], suggesting that the high-molecular-weight HA within the HA-Irinotecan could be exerting some form of antiangiogenic effect.…”

Section: Discussionsupporting

confidence: 71%

A Pilot Human Evaluation of a Formulation of Irinotecan and Hyaluronic Acid in 5-Fluorouracil-Refractory Metastatic Colorectal Cancer Patients

Gibbs

Brown

et al. 2008

Chemotherapy

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Background: Preclinical data demonstrate that the polysaccharide hyaluronic acid (HA) acts as a macromolecular carrier for chemotherapeutic drugs. In these studies the formulation of HA and irinotecan reduced treatment-related toxicity and improved efficacy via the preferential delivery of irinotecan to the tumor and lymph nodes. This study was designed as a first-in-man investigation of the safety and pharmacokinetics of irinotecan when administered within the HA-Irinotecan formulation. Methods: 5-Fluorouracil refractory metastatic colorectal cancer patients were intravenously treated with HA-Irinotecan (300 mg/m² irinotecan with 1,000 mg/m² HA) on day 1 of a 21-day cycle. After safety was demonstrated, the irinotecan dose was increased to 350 mg/m² with maintenance of the HA at 1,000 mg/m².DELETEResults: Twelve patients were treated with HA-Irinotecan. Overall toxicity was low, with an 8 and 17% incidence of grade lll/lV diarrhea and neutropenia, respectively. No grade III/IV nausea or vomiting was observed. Seventeen percent of patients had a partial response and 50% experienced stable disease, indicating that the efficacy of the irinotecan was maintained. Median survival was 16.6 months, while median progression-free survival was 6.2 months. Conclusion: HA-Irinotecan containing standard doses of irinotecan can be safely administered to patients. Comparison to historical irinotecan data suggests HA-Irinotecan may have a greater margin of safety without compromising anticancer activity.

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“…1). Since then, degradation products of specific size (3-10 disaccharide units; o-HA) were shown to stimulate vascular EC proliferation (West and Kumar, 1989;Deed et al, 1997;Slevin et al, 1998Slevin et al, , 2002Slevin et al, , 2004, migration (Sattar et al, 1994), collagen synthesis (Rooney et al, 1993), sprout formation (Montasano et al, 1996), and angiogenesis in rat skin (Sattar et al, 1994), myocardial infarction and in cryo-injured skin graft model (Lees et al, 1995).…”

Section: Ha and Angiogenesismentioning

confidence: 99%