Selective inhibition of spontaneous pulmonary metastasis of Lewis lung carcinoma by 5'-deoxy-5-fluorouridine.
5'-deoxy-5-fluorouridine (5'-FUdR) is a cytostatic that is biotransformed to 5-fluorouracil (5-FUra) by pyrimidine nucleoside phosphorylase (PyNPase), the expression of which is up-regulated by tumor necrosis factor alpha (TNF alpha), interleukin-1 alpha (IL-1 alpha) and interferon gamma (IFN gamma). In Lewis lung carcinoma (LLC) cell cultures, these inflammatory cytokines up-regulated the expression of type-IV collagenase, metastatic factor, as well as PyNPase and consequently enhanced the antiproliferative activity of 5'-FUdR. However, the activity of 5-FUra was not enhanced. It appears that 5'-FUdR selectively kills highly metastatic cells which are exposed to these intrinsic cytokines in tumor tissues, because of their high PyNPase activity. In fact, 5'-FUdR inhibited the spontaneous metastasis of LLC from the s.c. inoculation site to the lung. When 5'-FUdR was given during the process of metastasis it greatly reduced the number of tumor nodules in the lung even at doses 46 times lower than those inhibiting the primary tumor growth. In addition, 5'-FUdR, but not 5-FUra, lowered type-IV collagenase levels in the tumors at the low dose showing only anti-metastatic activity. On the other hand, 5-FUra showed anti-metastatic activity at doses similar to or only several times lower than those inhibiting the primary tumor growth.
Ishikawa
T
T
Department of Oncology, Nippon Roche Research Center, Kanagawa, Japan.
Ura
M
M
Yamamoto
T
T
Tanaka
Y
Y
Ishitsuka
H
H
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018827:Carcinoma, Lewis Lung / Q000201:enzymology / Q000517:prevention & control* / Q000556:secondary*; D002455:Cell Division / Q000187:drug effects; D017364:Collagenases / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology; D004357:Drug Synergism; D005467:Floxuridine / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000201:enzymology / Q000517:prevention & control* / Q000556:secondary*; D008297:Male; D020780:Matrix Metalloproteinase 9; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010430:Pentosyltransferases / Q000187:drug effects / Q000378:metabolism; D057845:Pyrimidine Phosphorylases; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D000970:Antineoplastic Agents; D016207:Cytokines; D005467:Floxuridine; D010430:Pentosyltransferases; D057845:Pyrimidine Phosphorylases; D017364:Collagenases; D020780:Matrix Metalloproteinase 9; C025034:doxifluridine