The topoisomerase II-inhibitor NC-190 reduces the level of thymidine kinase mRNA in murine tumor cells.
The novel antitumor compound NC-190 strongly inhibited the growth of FM3A cells with an IC50 of 0.019 microg/ml (0.042 microM) when cultured with NC-190 for 48 h. NC-190 potently suppressed DNA synthesis, with 90% inhibition observed at 0.1 microg/ml of NC-190. RNA and protein syntheses were also suppressed under the same conditions, but to a lesser extent. We then measured the cellular enzymatic activities of DNA polymerase alpha, RNA polymerase, thymidine kinase, thymidylate synthase and Leu-tRNA synthetase of FM3A cells cultured with or without NC-190. Of these 5 enzymes, the activity of thymidine kinase was most strongly suppressed by NC-190, by 77%. Although NC-190 did not directly inhibit the activitiy of thymidine kinase in a cell-free system, expression of mRNA of thymidine kinase was suppressed by 75% in NC-190-treated cells. These results indicate that NC-190 can suppress the expression of the gene for thymidine kinase and the inhibition of thymidine kinase contributes to the inhibition of cell growth by NC-190 together with the inhibition of topoisomerase II.
Samata
Kazunori
K
Medicinal Research Laboratories, Taisho Pharmaceutical. Co., Ltd., 1-403, Yoshino-cho, Saitama-shi, Saitama 330-8530, Japan.
Yamagishi
Takehiro
T
Ikeda
Tomotake
T
Kuraishi
Aiko
A
Nakaike
Shiro
S
Tanaka
Makoto
M
Kashiwagi
Keiko
K
Igarashi
Kazuei
K
D000818:Animals; D002453:Cell Cycle; D002455:Cell Division; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000473:pathology; D051379:Mice; D010619:Phenazines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D013937:Thymidine Kinase / Q000235:genetics*; D059005:Topoisomerase II Inhibitors
D004791:Enzyme Inhibitors; D010619:Phenazines; D012333:RNA, Messenger; D059005:Topoisomerase II Inhibitors; C059048:NC 190; D013937:Thymidine Kinase