Antitumor activity of a novel chimera tumor necrosis factor (TNF-STH) constructed by connecting rTNF-S with thymosin beta 4 against murine syngeneic tumors.
We have shown the in vivo usefulness of a novel chimera tumor necrosis factor (TNF), called rTNF-STH, which was constituted with human thymosin beta 4 and recombinant human TNF-SAM1. Tumor necrosis was induced by intravenous injection of a smaller amount of rTNF-STH (1 x 10(3) U/mouse, 0.67 microgram/mouse) than rTNF-alpha or rTNF-S (1 x 10(4) U/mouse, 2.5-5 micrograms/mouse). Significant antitumor effects of rTNF-STH to Meth A fibrosarcoma, B16 melanoma, MH134 hepatoma, or Lewis lung carcinoma (3LL) were observed by systemic injection of rTNF-STH at the maximum tolerable dose of 1 x 10(4) U/mouse (6.7 micrograms/mouse); this dose did not cause regression of tumors by conventional rTNF-alpha. rTNF-STH showed a significant prolongation of its half-life in serum. The average calculated half-life of the chimera protein is about 110 min, which is 15 times longer than that of original TNF-SAM1 (7.5 min). On the basis of this prolongation of half-life of rTNF-STH and its efficient hemorrhagic necrotic activity, the antitumor effect of rTNF-STH--as compared with that of the known TNF species--is discussed. Findings indicate that use of the chimera protein to alter the N-terminal region of TNF may be a promising approach to obtain molecules that more favorably attack tumors and other diseases than conventional rTNFs.
Noguchi
K
K
Biotechnology Research Center, Teikyo University, Kanagawa, Japan.
Inagawa
H
H
Tsuji
Y
Y
Morikawa
A
A
Mizuno
D
D
Soma
G
G
D000818:Animals; D005354:Fibrosarcoma / Q000188:drug therapy / Q000473:pathology; D006207:Half-Life; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy; D008175:Lung Neoplasms / Q000188:drug therapy; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009336:Necrosis; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D013947:Thymosin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000099201:Thymosin beta(4)
D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D013947:Thymosin; D014409:Tumor Necrosis Factor-alpha; D000099201:Thymosin beta(4)