In vivo and in vitro evaluation of combretastatin A-4 and its sodium phosphate prodrug.

2.50
Hdl Handle:
http://hdl.handle.net/10541/90790
Title:
In vivo and in vitro evaluation of combretastatin A-4 and its sodium phosphate prodrug.
Authors:
Grosios, K; Holwell, S E; McGown, Alan T; Pettit, G R; Bibby, M C
Abstract:
The anti-tumour effects and mechanism of action of combretastatin A-4 and its prodrug, combretastatin A-4 disodium phosphate, were examined in subcutaneous and orthotopically transplanted experimental colon tumour models. Additionally, the ability of these compounds to directly interfere with endothelial cell behaviour was also examined in HUVEC cultures. Combretastatin A-4 (150 mg kg(-1), intraperitoneally (i.p.)) and its water-soluble prodrug (100 mg kg(-1), i.p.) caused almost complete vascular shutdown (at 4 h), extensive haemorrhagic necrosis which started at 1 h after treatment and significant tumour growth delay in MAC 15A subcutaneous (s.c.) colon tumours. Similar vascular effects were obtained in MAC 15 orthotopic tumours and SW620 human colon tumour xenografts treated with the prodrug. More importantly, in the orthotopic models, necrosis was seen in vascularized metastatic deposits but not in avascular secondary deposits. The possible mechanism giving rise to these effects was examined in HUVEC cells. Here cellular networks formed in type I calf-skin collagen layers and these networks were completely disrupted when incubated with a non-cytotoxic concentration of combretastatin A-4 or its prodrug. This effect started at 4 h and was complete by 24 h. The same non-cytotoxic concentrations resulted in disorganization of F-actin and beta-tubulin at 1 h after treatment. In conclusion, combretastatin A-4 and its prodrug caused extensive necrosis in MAC 15A s.c. and orthotopic colon cancer and metastases, resulting in anti-tumour effects. Necrosis was not seen in avascular tumour nodules, suggesting a vascular mechanism of action.
Affiliation:
Clinical Oncology Unit, University of Bradford, West Yorkshire, UK.
Citation:
In vivo and in vitro evaluation of combretastatin A-4 and its sodium phosphate prodrug. 1999, 81 (8):1318-27 Br. J. Cancer
Journal:
British Journal of Cancer
Issue Date:
Dec-1999
URI:
http://hdl.handle.net/10541/90790
DOI:
10.1038/sj.bjc.6692174
PubMed ID:
10604728
Type:
Article
Language:
en
ISSN:
0007-0920
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorGrosios, Ken
dc.contributor.authorHolwell, S Een
dc.contributor.authorMcGown, Alan Ten
dc.contributor.authorPettit, G Ren
dc.contributor.authorBibby, M Cen
dc.date.accessioned2010-01-28T11:22:29Z-
dc.date.available2010-01-28T11:22:29Z-
dc.date.issued1999-12-
dc.identifier.citationIn vivo and in vitro evaluation of combretastatin A-4 and its sodium phosphate prodrug. 1999, 81 (8):1318-27 Br. J. Canceren
dc.identifier.issn0007-0920-
dc.identifier.pmid10604728-
dc.identifier.doi10.1038/sj.bjc.6692174-
dc.identifier.urihttp://hdl.handle.net/10541/90790-
dc.description.abstractThe anti-tumour effects and mechanism of action of combretastatin A-4 and its prodrug, combretastatin A-4 disodium phosphate, were examined in subcutaneous and orthotopically transplanted experimental colon tumour models. Additionally, the ability of these compounds to directly interfere with endothelial cell behaviour was also examined in HUVEC cultures. Combretastatin A-4 (150 mg kg(-1), intraperitoneally (i.p.)) and its water-soluble prodrug (100 mg kg(-1), i.p.) caused almost complete vascular shutdown (at 4 h), extensive haemorrhagic necrosis which started at 1 h after treatment and significant tumour growth delay in MAC 15A subcutaneous (s.c.) colon tumours. Similar vascular effects were obtained in MAC 15 orthotopic tumours and SW620 human colon tumour xenografts treated with the prodrug. More importantly, in the orthotopic models, necrosis was seen in vascularized metastatic deposits but not in avascular secondary deposits. The possible mechanism giving rise to these effects was examined in HUVEC cells. Here cellular networks formed in type I calf-skin collagen layers and these networks were completely disrupted when incubated with a non-cytotoxic concentration of combretastatin A-4 or its prodrug. This effect started at 4 h and was complete by 24 h. The same non-cytotoxic concentrations resulted in disorganization of F-actin and beta-tubulin at 1 h after treatment. In conclusion, combretastatin A-4 and its prodrug caused extensive necrosis in MAC 15A s.c. and orthotopic colon cancer and metastases, resulting in anti-tumour effects. Necrosis was not seen in avascular tumour nodules, suggesting a vascular mechanism of action.en
dc.language.isoenen
dc.subjectExperimental Canceren
dc.subjectAntitumour Drug Screening Assaysen
dc.subject.meshAnimals-
dc.subject.meshCell Division-
dc.subject.meshCells, Cultured-
dc.subject.meshCollagen-
dc.subject.meshDrug Screening Assays, Antitumor-
dc.subject.meshHumans-
dc.subject.meshMice-
dc.subject.meshMice, Nude-
dc.subject.meshNeoplasms, Experimental-
dc.subject.meshNeovascularization, Pathologic-
dc.subject.meshProdrugs-
dc.subject.meshStilbenes-
dc.titleIn vivo and in vitro evaluation of combretastatin A-4 and its sodium phosphate prodrug.en
dc.typeArticleen
dc.contributor.departmentClinical Oncology Unit, University of Bradford, West Yorkshire, UK.en
dc.identifier.journalBritish Journal of Canceren

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