Suppression of serum tumour necrosis factor-alpha by thalidomide does not lead to reversal of tumour vascular collapse and anti-tumour activity of 5,6-dimethylxanthenone-4-acetic acid.
The antitumour agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA), developed in this laboratory as a potent analogue of flavone acetic acid (FAA), has a novel antitumour action involving both immune and vascular components. DMXAA induces the synthesis of tumour necrossi factor-alpha (TNF) and it has been hypothesised that this mediates its selective reduction of tumour blood flow and consequent induction of tumour necrosis. Unexpectedly, the drug thalidomide, while reducing the serum TNF response to DMXAA, potentiates its antitumour effect. We have investigated this in the MDAH-MCa-4 mammary carcinoma model, comparing it to previous data with the Colon 38 adenocarcinoma. We have related DMXAA-induced blood flow changes in the MCa-4 tumour to tumour growth delay, serum TNF and extractable TNF from tumour tissue. We have also compared the effect of thalidomide (387 mumol/kg) on DMXAA (80 mumol/kg) with that of a monoclonal anti-TNF antibody (50 micrograms/mouse). We find that tumour blood flow reduction is strongly correlated with tumour growth delay. Coadministration of anti-TNF antibody abolishes serum TNF levels and slightly reduces the antitumour effects of DMXAA. While tumour growth delay is not correlated with serum induced TNF levels, it is related to tumour TNF levels. We conclude that while the data are consistent with TNF being the principal mediator of the action of DMXAA, serum TNF levels do not reflect the antitumour response.
Browne
W L
WL
Auckland Cancer Society Research Centre, University of Auckland School of Medicine, New Zealand.
Wilson
W R
WR
Baguley
B C
BC
Ching
L M
LM
D000230:Adenocarcinoma; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D003110:Colonic Neoplasms; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000097:blood / Q000098:blood supply* / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009336:Necrosis; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000517:prevention & control; D012039:Regional Blood Flow / Q000187:drug effects; D013792:Thalidomide / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D014966:Xanthenes / Q000627:therapeutic use*; D044004:Xanthones
D000970:Antineoplastic Agents; D014409:Tumor Necrosis Factor-alpha; D014966:Xanthenes; D044004:Xanthones; C066668:vadimezan; D013792:Thalidomide