Modulation of 5-fluorouracil cytotoxicity through thymidylate synthase and NF-kappaB down-regulation and its application on the radiolabelled iododeoxyuridine therapy on human hepatoma cell.
The inhibition of thymidylate synthase (TS) by 5-fluorouracil (5-FU) was known to increase the incorporation of radiolabelled iododeoxyuridine (IdUrd) into DNA. The relatively non-toxic compounds such as thiol-containing antioxidant pyrrolidinodithiocarbamte (PDTC) or aromatic fatty acid phenylbutyrate (PB) had been reported to enhance the cytotoxic efficacy of 5-FU. We designed a novel strategy through triplet combination of PB, PDTC and 5-FU to increase the radiolabelled IdUrd uptake and investigated the underlying mechanisms. The growth inhibition and [(125)I]IdUrd-DNA incorporation by PB, PDTC, 5-FU in different combinations were tested on parent or p21(Waf1) transfected Hep3B cells. The combination of PB and PDTC was more effective in enhancing 5-FU cytotoxicity than either drug alone. The combination of PB/PDTC and 5-FU blocked cells in S-phase and resulted in 8.5-fold increase of radiolabelled IdUrd-DNA incorporation. The transfection of p21(Waf1) did not change the general pattern of enhancement. Intriguingly, the combination of PB and PDTC effectively down-regulated NF-kappaB and TS and prevented their up-regulation from 5-FU treatment than either drug alone through a p21(Waf1)-independent mechanism. Based on this strategy, the 3-drug combination offered potential for improved radiolabelled IdUrd molecular radiotherapy for hepatoma treatment.
Wang
Hsin-Ell
HE
Institute of Radiological Sciences, National Yang-Ming University, Taipei 112, Taiwan.
Wu
Hui-Chuan
HC
Kao
Shang-Jyh
SJ
Tseng
Fan-Wei
FW
Wang
Yu-Shan
YS
Yu
Hung-Man
HM
Chou
Shun-Lan
SL
Yen
Sang-Hue
SH
Chi
Kwan-Hwa
KH
D006528:Carcinoma, Hepatocellular / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D007065:Idoxuridine / Q000627:therapeutic use*; D007457:Iodine Radioisotopes / Q000627:therapeutic use*; D008113:Liver Neoplasms / Q000532:radiotherapy*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010654:Phenylbutyrates / Q000494:pharmacology; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology; D013859:Thiocarbamates / Q000494:pharmacology; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*
D007457:Iodine Radioisotopes; D016328:NF-kappa B; D010654:Phenylbutyrates; D013859:Thiocarbamates; C066229:prolinedithiocarbamate; D011392:Proline; D013940:Thymidylate Synthase; D007065:Idoxuridine; D005472:Fluorouracil