Tumor selective antivascular effects of the novel antimitotic compound ABT-751: an in vivo rat regional hemodynamic study.
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.
Segreti
Jason A
JA
Pharmaceutical Discovery, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA. jason.segreti@abbott.com
Polakowski
James S
JS
Koch
Kristin A
KA
Marsh
Kennan C
KC
Bauch
Joy L
JL
Rosenberg
Saul H
SH
Sham
Hing L
HL
Cox
Bryan F
BF
Reinhart
Glenn A
GA
D000008:Abdominal Neoplasms / Q000098:blood supply* / Q000662:veterinary; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D005910:Glioma / Q000098:blood supply* / Q000662:veterinary; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009374:Neoplasms, Experimental / Q000098:blood supply; D011728:Pyridones; D051381:Rats; D011916:Rats, Inbred F344; D013449:Sulfonamides / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism; D014655:Vascular Resistance / Q000187:drug effects*
C490492:ABT751; D000970:Antineoplastic Agents; D011728:Pyridones; D013449:Sulfonamides; D014404:Tubulin; C115200:ABT 255