Anti-tumor and anti-vascular effects of the novel tubulin-binding agent combretastatin A-1 phosphate.
The combretastatins are derived from an African medicinal plant Combretum caffrum (Combretaceae). They have previously been shown to be potent inhibitors of microtubule assembly that cause marked haemorrhagic necrosis in murine subcutaneous tumors. Promising clinical trial results with combretastatin A-4 phosphate led to this investigation of the anti-tumor and anti-vascular effects of a close structural analog, combretastatin A-1 phosphate. This compound caused identical disruption of the tubulin cytoskeleton in HUVECs in vitro at similar concentrations and duration of exposure as combretastatin A-4 phosphate. Treatment of a well-vascularised murine colon adenocarcinoma (MAC 29) with an effective dose (150 mg/kg) of combretastatin A-1 phosphate resulted in a dramatic decrease in functional vascular volume 2 hours after administration. Vascular shutdown was complete within 4 hours after treatment apart from in small areas of the tumor periphery. Morphological examination of hepatic deposits of HT29 and DLD-1 human colon tumors in nude mice demonstrated that combretastatin A-1 phosphate displays greater anti-tumor effects than the A-4 analog at the same dose and this order of activity (A-1 > A-4) is mirrored in the subcutaneous site with the same tumor type. In summary, combretastatin A-1 phosphate can exert its anti-tumor action via an anti-vascular mechanism. The results indicate that, despite having similar in vitro anti-tubulin properties, combretastatin A-1 phosphate seems to have greater in vivo anti-tumor activity than combretastatin A-4 phosphate at the same doses and may therefore be more successful in the clinic.
Holwell
S E
SE
Cancer Research Unit, University of Bradford, West Yorkshire, BD7 1DP, U.K.
Cooper
P A
PA
Thompson
M J
MJ
Pettit
G R
GR
Lippert
L W
LW
Martin
S W
SW
Bibby
M C
MC
D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D005260:Female; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000556:secondary; D051379:Mice; D010755:Organophosphates / Q000494:pharmacology; D013267:Stilbenes / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D010755:Organophosphates; D013267:Stilbenes; D014404:Tubulin; C063690:combretastatin A-1; C058728:fosbretabulin