1-(3-C-Ethynyl-beta-D-ribo-pentofuranosyl)cytosine (ECyd, TAS-106), a novel potent inhibitor of RNA polymerase, potentiates the cytotoxicity of CDDP in human cancer cells both in vitro and in vivo.
1-(3-C-Ethynyl-beta-D-ribo-pentofuranosyl)cytosine (ECyd, TAS-106) is a novel antitumor ribonucleoside that inhibits RNA polymerase. In the present study, we investigated the cellular and molecular interactions between TAS-106 and cisplatin (CDDP) in vitro using A549 human lung cancer cells and the in vivo antitumor effect of combined treatment using OCC-1 and LX-1 human tumor xenografts. The treatment effects were determined by evaluating cytotoxicity, the cell cycle distribution, apoptosis induction and the expression of checkpoint-associated proteins. In vitro, the combination of TAS-106 and CDDP synergistically inhibited the growth of A549 cells, as determined using isobologram analysis. TAS-106 potently inhibited the expression of Chk1 protein and the phosphorylation of Chk1 and Chk2. Moreover, based on the inhibition of checkpoint-associated protein, TAS-106 abrogated the CDDP-induced S- and G2M-checkpoints and induced apoptosis in A549 cells. In vivo, TAS-106 alone showed antitumor activity; however, its combination with CDDP significantly enhanced the growth inhibition of OCC-1 and LX-1 tumors. Moreover, combination therapy with TAS-106 and CDDP in the OCC-1 xenograft model resulted in significant life-prolongation. These findings provide a rationale for combination chemotherapy using TAS-106 and CDDP in clinical settings.
Hanno Research Center, Taiho Pharmaceutical Co., Ltd., Hanno-city, Saitama 357-8527, Japan. h-kazuno@taiho.co.jp
Hiromi
H
Kazuno
Akio
A
Fujioka
Masakazu
M
Fukushima
Yusuke
Y
Wataya
Akira
A
Matsuda
Takuma
T
Sasaki
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D002945:Cisplatin / Q000008:administration & dosage* / Q000494:pharmacology; D003562:Cytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D011923:Rats, Nude; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
C103084:1-(3-C-ethynylribopentofuranosyl)cytosine; D004791:Enzyme Inhibitors; D003562:Cytidine; D012321:DNA-Directed RNA Polymerases; D002945:Cisplatin