Mode of antitumor action of recombinant human tumor necrosis factor on the sarcoma Meth A transplanted in the mouse.
The mode of antitumor action of rHu-TNF was elucidated in BALB/c mice bearing Meth A fibrosarcoma 7 days after transplantation with respect to time course, dose-response relationships and selectivity of the effects. The maximal cytotoxic effect on tumor cells revealed by inhibition of DNA synthesis and maximal lesional effect on tumor vasculature revealed by change in blood pool-size in the tissue were detected at 30 min and 1 h after administration of rHu-TNF, respectively. The dose-response relationship between cytotoxic and tumoricidal effects of rHu-TNF was irrespective of administration route. ED50s of these antitumor effects after i.v. administration of rHu-TNF were about 50 times as high as ED50s after i.t. administration. ED50 of i.t. given rHu-TNF for vascular effect was about 20 times as high as that for cytotoxicity while ED50 of i.v. rHu-TNF for vascular effect was only 2-3 times as high as that for cytotoxicity. The whole body autoradiographies with [125I]HSA given i.v. to see the blood influx into tumor tissue and [14C]thymidine given i.v. to see DNA synthesis in the whole body after administration of rHu-TNF revealed that the distribution of radioactivity was markedly changed in the tumor alone without any detectable change in other whole body tissues. In conclusion, the in vivo antitumor effect of rHu-TNF given i.t. or i.v. appears to be exerted through the direct action on Meth A sarcoma rather than indirectly on tumor vasculature. Under present conditions, the effect of rHu-TNF in the whole body tissues seems rather selective on cells and vasculature of the tumor.
Miyazaki
H
H
Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Osaka, Japan.
Iida
M
M
Matsunaga
Y
Y
Fujii
T
T
Nambu
K
K
Amejima
H
H
Oh-e
Y
Y
Furukawa
H
H
Matsui
Y
Y
Sohmura
Y
Y
D000818:Animals; D000970:Antineoplastic Agents; D001345:Autoradiography; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D005260:Female; D007457:Iodine Radioisotopes; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000494:pharmacology; D012513:Sarcoma, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000493:pharmacokinetics / Q000494:pharmacology*
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D007457:Iodine Radioisotopes; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha