RB:
Damn website hasn't been updated much in the last year.......
oxigene.com
We should follow Landuyt closely. There's always the chance that a detailed publication will show up that the company chooses not to publicize. I'm a bit less enthusiastic now that I see that Combretastuff is a tubulin inhibitor. BTW.... a medline search on G. Pettit will make MOGN fans drool.......
"Combretastatin A-4, a naturally-occurring substance, was identified and isolated by Dr. George R. Pettit, Regents Professor of Chemistry, and
his colleagues at ASU, from the South African tree Combretum caffrum."............
Br J Cancer 1996 Jul;74 Suppl 27:S86-8
Antivascular approaches to solid tumour therapy: evaluation of tubulin
binding agents.
Chaplin DJ, Pettit GR, Parkins CS, Hill SA
Tumour Microcirculation Group, Gray Laboratory Cancer Research Trust, Mount Vernon Hospital, Northwood, Middlesex.
[Medline record in process]
We have assessed the vascular effects of vinblastine and four other tubulin binding agents (dolastatin 10, dolastatin 15,
combretastatin A1 and combretastatin A4), which are awaiting clinical evaluation. All five agents induce a reduction in tumour
blood flow as measured by uptake of RbCI 24 h post drug administration. The degree of reduction ranged from 50% with
combretastatin A1 to 90% with dolastatin 10. These reductions were similar to that seen with flavone acetic acid (FAA) and
indicate that antivascular effects are a common feature of tubulin binding agents. We subsequently evaluated whether the blood
flow reductions, induced by FAA and vinblastine, could be used to enhance the activity of the bioreductive drug tirapazamine.
Since the kinetics and extent of blood flow reductions induced by the agents is comparable, similar therapeutic response was
expected. Potentiation was only evident with FAA, indicating that this effect is not directly related to killing of hypoxic tumour
cells induced as a consequence of blood flow reduction.
Cancer Res 1997 May 15;57(10):1829-34
Combretastatin A-4, an agent that displays potent and selective toxicity
toward tumor vasculature.
Dark GG, Hill SA, Prise VE, Tozer GM, Pettit GR, Chaplin DJ
Gray Laboratory Cancer Research Trust, Mount Vernon Hospital, Northwood, Middlesex, United Kingdom.
Selective induction of vascular damage within tumors represents an emerging approach to cancer treatment. Histological studies
have shown that several tubulin-binding agents can induce vascular damage within tumors but only at doses approximating the
maximum tolerated dose, which has limited their clinical applicability. In this study, we show that the combretastatin A-4
prodrug induces vascular shutdown within tumors at doses less than one-tenth of the maximum tolerated dose. In vitro studies
indicate that a short drug exposure results in profound long-term antiproliferative/cytotoxic effects against proliferating
endothelial cells but not cells that are quiescent prior to and during drug exposure. Vascular shutdown, within experimental and
human breast cancer models in vivo following systemic drug administration, was demonstrated with a reduction in functional
vascular volume of 93% at 6 h following drug administration and persisted over the next 12 h, with corresponding histology
consistent with hemorrhagic necrosis resulting from vascular damage. These actions against tumor vasculature and the broad
therapeutic window demonstrate the clinical potential of these drugs and warrant further study to elucidate the mechanisms
responsible for the antivascular effects of combretastatin A-4. |
