Thalidomide increases both intra-tumoural tumour necrosis factor-alpha production and anti-tumour activity in response to 5,6-dimethylxanthenone-4-acetic acid.
5,6-Dimethylxanthenone-4-acetic acid (DMXAA), synthesized in this laboratory and currently in phase I clinical trial, is a low molecular weight inducer of tumour necrosis factor-alpha (TNF-alpha). Administration of DMXAA to mice with established transplantable tumours elicits rapid vascular collapse selectively in the tumour, followed by extensive haemorrhagic necrosis mediated primarily through the production of TNF-alpha. In this report we have investigated the synthesis of TNF-alpha mRNA in hepatic, splenic and tumour tissue. Co-administration of thalidomide with DMXAA increased anti-tumour activity and increased intra-tumoural TNF-alpha production approximately tenfold over that obtained with DMXAA alone. Thalidomide increased splenic TNF-alpha production slightly but significantly decreased serum and hepatic levels of TNF-alpha induced with DMXAA. Lipopolysaccharide (LPS) induced 300-fold higher serum TNF-alpha than did DMXAA at the maximum tolerated dose, but induced similar amounts of TNF-alpha in spleen, liver and tumour. Splenic TNF-alpha activity induced with LPS was slightly increased with thalidomide, but serum and liver TNF-alpha levels were suppressed. Thalidomide did not increase intra-tumoural TNF-alpha production induced with LPS, in sharp contrast to that obtained with DMXAA. While thalidomide improved the anti-tumour response to DMXAA, it had no effect on the anti-tumour action of LPS that did not induce a significant growth delay or cures against the Colon 38 tumour. The increase in the anti-tumour action by thalidomide in combination with DMXAA corresponded to an increase in intra-tumoural TNF-alpha production. Co-administration of thalidomide may represent a novel approach to improving selective intra-tumoural TNF-alpha production and anti-tumour efficacy of DMXAA.
Cao
Z
Z
Auckland Cancer Society Research Centre, University of Auckland School of Medicine, New Zealand.
Joseph
W R
WR
Browne
W L
WL
Mountjoy
K G
KG
Palmer
B D
BD
Baguley
B C
BC
Ching
L M
LM
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009368:Neoplasm Transplantation; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D013792:Thalidomide / Q000008:administration & dosage / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D014966:Xanthenes / Q000008:administration & dosage / Q000494:pharmacology*; D044004:Xanthones
D000970:Antineoplastic Agents; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D014966:Xanthenes; D044004:Xanthones; C066668:vadimezan; D013792:Thalidomide