Induction of tumor necrosis factor-alpha messenger RNA in human and murine cells by the flavone acetic acid analogue 5,6-dimethylxanthenone-4-acetic acid (NSC 640488).
The investigational antitumor agent, 5,6-dimethylxanthenone-4-acetic acid (5,6-MeXAA; NSC 640488) induced greater expression of tumor necrosis factor-alpha (TNF-alpha) mRNA in murine spleen cells in vivo at its optimal dose of 27.5 mg/kg than flavone acetic acid (FAA; NSC 347512) at its optimal dose of 220 mg/kg. Up-regulation of TNF-alpha mRNA was obtained using 5,6-MeXAA in vitro in cultures of murine splenocytes, the murine J774 macrophage cell line, and the human HL-60 myelomonocytic leukemia cell line. Maximal induction occurred at a 5,6-MeXAA concentration of 200 micrograms/ml for both murine J774 and human HL-60 cells. A direct comparison of FAA and 5,6-MeXAA (100-600 micrograms/ml) to stimulate TNF-alpha mRNA in HL-60 cells showed activity by 5,6-MeXAA at all doses but minimal activity with FAA. The results demonstrate that 5,6-MeXAA is equally potent in up-regulating TNF-alpha mRNA in human and murine cells of the monocyte/macrophage lineage, whereas FAA has demonstrable activity in murine cells only. The results suggest that 5,6-MeXAA would be a more active clinical agent than FAA because TNF-alpha induction appears to be a critical factor in the antitumor effects of this class of compounds.
Ching
L M
LM
Cancer Research Laboratory, University of Auckland School of Medicine, New Zealand.
Joseph
W R
WR
Crosier
K E
KE
Baguley
B C
BC
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000096:biosynthesis*; D013045:Species Specificity; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D014966:Xanthenes / Q000494:pharmacology*; D044004:Xanthones
D000970:Antineoplastic Agents; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D014966:Xanthenes; D044004:Xanthones; C066668:vadimezan