Tumour-selective antivascular effects of the novel anti-mitotic compound A-318315: An in vivo rat regional haemodynamic study.
1. It has been shown that tubulin-binding agents can destabilize cellular microtubules and suppress tumour growth; but it has also become apparent that some compounds can exert anti-vascular effects within the neovasculature of a solid tumour. To date, the difficulty with these targets has been the ability to selectivity induce vascular damage to the tumour while leaving normal vasculature unaffected. The data presented here characterizes the in vivo, tumour selective, anti-vascular effects of the novel tubulin-binding agent A-318315. 2. To that purpose, we have used an anaesthetized in vivo rat model designed to quantify acute changes in regional vascular resistance (VR) in both tumour and non-tumour vascular beds, simultaneously. Tissue-isolated tumours (approximately 1.25 gm) with blood flow supplied by a single epigastric artery were grown in the hindlimb of adult male rats. Blood flow to the tumour, mesenteric, renal and normal (non-tumour epigastric) arteries was measured pre-dose and post-dose under anaesthesia. 3. A-318315 was tested at 3, 10 and 30 mg/kg, i.v. These doses produced modest, transient increases in mean arterial pressure with little to no effect on heart rate. At peak effect, tumour VR increased to 175 +/- 47, 337 +/- 77 and 751 +/- 151% above the baseline, for the 3, 10 and 30 mg/kg doses, respectively, whereas VR was only modestly and transiently increased in normal epigastric (88 +/- 19%), mesenteric (33 +/- 3.3%) and renal arteries (17 +/- 8.6%). 4. These data demonstrate that A-318315 produces marked reductions in tumour blood flow in the rat at doses that exert minor effects on normal vascular function.
Abbott Laboratories, Global Pharmaceutical Research and Development, Abbott Park, IL, USA. Jason.Segreti@abbott.com
Jason A
JA
Segreti
Kristin A
KA
Brooks
Kennan C
KC
Marsh
Joy L
JL
Bauch
Yan
Y
Lan
C
C
Thomas Lin
Saul H
SH
Rosenberg
Hing L
HL
Sham
Glenn A
GA
Reinhart
Bryan F
BF
Cox
James S
JS
Polakowski
D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D050256:Antimitotic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D007211:Indoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D015394:Molecular Structure; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D011916:Rats, Inbred F344; D013449:Sulfonamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D014404:Tubulin / Q000378:metabolism; D014655:Vascular Resistance / Q000187:drug effects
C552930:A-318315; D020533:Angiogenesis Inhibitors; D050256:Antimitotic Agents; D007211:Indoles; D013449:Sulfonamides; D014404:Tubulin