NB1011, a
phosphoramidate derivative of
(E)-5-(2-bromovinyl)-2'-deoxyuridine, is a novel small molecule
anticancer agent.
NB1011 is selectively active against
tumor cells expressing high levels of
thymidylate synthase (TS), a critical
enzyme in
DNA biosynthesis.
NB1011 is different from the current TS-targeted drugs, which require inhibition of TS to be effective, because
NB1011 cytotoxicity depends upon activation by TS. Here we report a dose-dependent, antitumor activity of
NB1011 against established
Tomudex-resistant
breast cancer (MCF7TDX) xenografts in athymic mice. Against 5-fluorouracil-resistant colon
carcinoma (H630R10) xenografts,
NB1011 was as efficacious as
irinotecan, a
drug recently approved for the treatment of 5-fluorouracil-resistant
colon cancer. To gain insight into the mechanisms
NB1011 uses to suppress cellular growth, we analyzed the downstream molecular events in the high TS-expressing MCF7TDX and RKOTDX cell lines upon
NB1011 treatment.
NB1011 treatment increased the
mRNA levels of p21, Bax, and GADD45. Furthermore,
NB1011 induced p53, p21, and Bax
proteins specifically in high TS-expressing
tumor cells, whereas no induction was observed in low TS-expressing
tumor cells (MCF7) or normal cells (WI38). Cell cycle analysis demonstrated that
NB1011 treatment of MCF7TDX and RKOTDX cells resulted in an accumulation of cells in the G2-M phase of the cell cycle. Altogether, our data indicate that the induction of the p53 target genes p21, bax, and GADD45, with a concomitant deregulation of the cell cycle, may represent one of the mechanisms by which
NB1011 exerts its growth-suppressive effects.