Abstract |
Tumour-specific vascularisation may be therapeutically approached in two different ways: by antiangiogenic treatments specifically directed to dividing and migrating endothelial cells, or by agents that target principally the inadequate and ill-structured tumour vasculature. Combretastatin A-4 phosphate (combreAp), a recently synthesised prodrug (OXiGENE, Lund, Sweden), is a vascular targeting agent of the latter kind. We evaluated the effect of a single intraperitoneal (i.p.) combreAp injection on the growth of rhabdomyosarcomas syngeneic in WAG/Rij rats. Different tumour volume groups, ranging between 0.1 and 27 cm(3), were selected to assess the relationship between the size at treatment time and the response to combreAp. A double combreAp treatment (2x25 mg/kg) was investigated within the same overall aim: the relationship between growth delay and tumour size. Our results show that the systemic administration of combreAp induces a clear-cut differential growth delay in the solid rat rhabdomyosarcomas: with very large tumours (>/= 14 cm(3)), a 17.6-fold stronger effect was measured than with very small tumours (<1 cm(3)). This is the 'inverse' of the volume-response seen with the conventional therapeutic approaches ( radiotherapy, chemotherapy or surgery). These combreAp antitumour responses were observed without treatment limiting systemic toxicity in the rats. With clinical digital subtraction angiography, using microsurgical cannulation of a major tumour draining vessel, and with histopathology, we demonstrate that growth delay is related to an early (within 3-6 h) and extensive breakdown of tumour blood vessels. The experiments involving a second injection also indicate a volume-dependent effect of combreAp in reducing the regrowth rate of small or large rhabdomyosarcomas. This significant differential volume-response obtained with 'selective' vascular targeting, stronger in larger tumours than smaller ones, suggests the potential of broadening the therapeutic window.
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Authors | W Landuyt, O Verdoes, D O Darius, M Drijkoningen, S Nuyts, J Theys, L Stockx, W Wynendaele, J F Fowler, G Maleux, W Van den Bogaert, J Anné, A van Oosterom, P Lambin |
Journal | European journal of cancer (Oxford, England : 1990)
(Eur J Cancer)
Vol. 36
Issue 14
Pg. 1833-43
(Sep 2000)
ISSN: 0959-8049 [Print] England |
PMID | 10974632
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antineoplastic Agents, Phytogenic
- Stilbenes
- fosbretabulin
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Topics |
- Angiography, Digital Subtraction
- Animals
- Antineoplastic Agents, Phytogenic
(therapeutic use)
- Cell Division
- Neovascularization, Pathologic
(drug therapy, pathology)
- Rats
- Rhabdomyosarcoma
(blood supply, drug therapy, pathology)
- Stilbenes
(therapeutic use)
- Tumor Cells, Cultured
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