Vascular targeting of solid tumours: a major 'inverse' volume-response relationship following combretastatin A-4 phosphate treatment of rat rhabdomyosarcomas

Tumour-specific vascularisation may be therapeutically approached in two di fferent ways. by antiangiogenic treatments specifically directed to dividin g and migrating endothelial cells, or by agents that target principally the inadequate and ill-structured tumour vasculature. Combretastatin A-4 phosp hate (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 rhabdom yosarcomas syngeneic in WAG/Rij rats. Different tumour volume groups, rangi ng between 0.1 and 27 cm(3), were selected to assess the relationship betwe en the size at treatment time and the response to combreAp. A double combre Ap treatment (2x25 mg/kg) was investigated within the same overall aim: the relationship between growth delay and tumour size. Our results show that t he systemic administration of combreAp induces a clear-cut differential gro wth delay in the solid rat rhabdomyosarcomas, with very large tumours (grea ter than or equal to 14 cm(3)), a 17.6-fold stronger effect was measured th an with very small tumours(< 1 cm(3)). This is the 'inverse' of the volume- response seen with the conventional therapeutic approaches (radiotherapy, c hemotherapy or surgery). These combreAp antitumour responses were observed without treatment limiting systemic toxicity in the rats. With clinical dig ital subtraction angiography, using microsurgical cannulation of a major tu mour draining vessel, and with histopathology, we demonstrate that growth d elay is related to an early (within 3-6 h) and extensive breakdown of tumou r blood vessels. The experiments involving a second injection also indicate a volume-dependent effect of combreAp in reducing the regrowth rate of sma ll or large rhabdomyosarcomas. This significant differential volume-respons e obtained with 'selective' vascular targeting, stronger in larger tumours than smaller ones, suggests the potential of broadening the therapeutic win dow. (C) 2000 Elsevier Science Ltd. All rights reserved.