Selective induction of vascular damage within a growing
tumor is a potentially important approach in the search for potent anticancer
therapeutics.
Tubulin-binding (
antimitotic) agents destabilize cellular microtubules, suppress
tumor growth, and exert antivascular effects with varying degrees of
tumor selectivity in preclinical models. The
tumor-selective, antivascular effects of
ABT-751, a novel, orally active
antimitotic agent, currently in phase II clinical development, were characterized in vivo in the present study. We developed an in vivo rat model designed to quantify acute changes in regional vascular resistance (VR) in both
tumor and non-
tumor vascular beds simultaneously. Tissue-isolated
tumors (1 g) with blood flow supplied by a single epigastric artery were grown in rats. Subsequently,
tumor blood flow was measured under
anesthesia in solid
tumors and also in mesenteric, renal, and normal epigastric arteries.
Phenylephrine-induced (1 micromol/kg) increases in VR were not different between
tumor and non-
tumor epigastric arteries, suggesting that
tumor vessels possess relatively normal vasoconstrictive function.
ABT-751 (3, 10, and 30 mg/kg; i.v.) produced modest transient increases in mean arterial pressure with no effect on heart rate.
Tumor VR increased to 75+/-36, 732+/-172, and 727+/-125% above baseline, respectively (P<0.05 for the 10 and 30 mg/kg doses), whereas VR in normal epigastric arteries was not significantly affected. Administration of
ABT-751 produced transient modest ( P<0.05) increases in mesenteric VR and no effect on renal VR. These results demonstrate that
ABT-751 produces marked reductions in
tumor blood flow in the intact rat at doses that exert negligible effects on normal vascular function.