期刊
BIOCHEMICAL PHARMACOLOGY
卷 69, 期 4, 页码 617-626出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2004.11.006
关键词
iododeoxyuridine; thymidylate synthase; 5-FU; PDTC; PB; NF-kappa B
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 [I-125]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. (C) 2004 Elsevier Inc. All rights reserved.
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