Combination chemotherapy of oral 5'-deoxy-5-fluorouridine and cisplatin in advanced gastric cancer: a phase II study

Ahn, Min; Han, Dong-Su; Sohn, Jung Ho; Jeon, Yong-Cheol; Jun, Dae-Won; Choi, Nayeon; Park, Hwon-Kyum; Baik, Hong-Kyu; Lee, Hong-Gi; Nam, Young-Soo; Choi, In‐Kyu

doi:10.3346/jkms.1998.13.6.612

Cited by 4 publications

(2 citation statements)

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“…Because cyclin E1 is a crucial regulator of the G 1 -S transition, any alteration in its expression could result in inappropriate G 1 cyclin function and have a critical effect on oncogenesis. This has been established by several independent studies showing aberrant expression of cyclin E1 in many human cancers, including colorectal, ovarian, breast, and gastric cancers (8)(9)(10)(11), and in several carcinogen-induced animal tumor models (12,13). A contributing role for cyclin E1 in mammary tumorigenesis was revealed in cyclin E1 transgenic mice, which exhibited an induction of mammary gland hyperplasia and carcinomas (14).…”

Section: Introductionmentioning

confidence: 99%

HuR Contributes to Cyclin E1 Deregulation in MCF-7 Breast Cancer Cells

Guo

Hartley

2006

Cancer Research

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Many cancers overexpress cyclin E1 and its tumor-specific low molecular weight (LMW) isoforms. However, the mechanism of cyclin E1 deregulation in cancers is still not well understood. We show here that the mRNA-binding protein HuR increases cyclin E1 mRNA stability in MCF-7 breast carcinoma cells. Thus, mRNA stabilization may be a key event in the deregulation of cyclin E1 in MCF-7 cells. Compared with MCF10A immortalized breast epithelial cells, MCF-7 cells overexpress full-length cyclin E1 and its LMW isoforms and exhibit increased cyclin E1 mRNA stability. Increased mRNA stability is associated with a stable adenylation state and an increased ratio of cytoplasmic versus nuclear HuR. UV crosslink competition and UV cross-link immunoprecipitation assays verified that HuR specifically bound to the cyclin E1 3 ¶-untranslated region. Knockdown of HuR with small interfering RNA (siRNA) in MCF-7 cells decreased cyclin E1 mRNA half-life (t 1/2 ) and its protein level: a 22% decrease for the full-length isoforms and 80% decrease for the LMW isoforms. HuR siRNA also delayed G 1 -S phase transition and inhibited MCF-7 cell proliferation, which was partially recovered by overexpression of a LMW isoform of cyclin E1. Overexpression of HuR in MCF10A cells increased cyclin E1 mRNA t 1/2 and its protein level. Taken together, our data show that HuR critically contributes to cyclin E1 overexpression and its growth-promoting function, at least in part by increasing cyclin E1 mRNA stability, which provides a new mechanism of cyclin E1 deregulation in breast cancer. (Cancer Res 2006; 66(16): 7948-56)

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Section: Introductionmentioning

confidence: 99%

HuR Contributes to Cyclin E1 Deregulation in MCF-7 Breast Cancer Cells

Guo

Hartley

2006

Cancer Research

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“…In a single randomized study, doxifluridine achieved some response in patients resistant to 5-FU, thus suggesting the absence of crossresistance between these two drugs [35]. Doxifluridine shows a more promising profile when associated to other compounds such as BVDU [36] or cisplatin [37].…”

Section: Fluoropyrimidine Drugs: the Older The Better Chemistry And mentioning

confidence: 97%

Thymidine Phosphorylase and Fluoropyrimidines Efficacy: A Jekyl and Hyde Story

Ciccolini¹,

Evrard²,

Cuq³

2004

CMCACA

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Thymidine phosphorylase (TP) is markedly upregulated in many solid tumors such as colorectal, breast and kidney cancers. Because TP is identical to platelet-derived endothelial cell growth factor, this enzyme is believed to have angiogenic properties, although the precise mechanisms through which it promotes neoangiogenesis are still not fully elucidated. TP is involved as well in the tumoral activation of widely prescribed pyrimidine-derived antimetabolites such as 5-FU, 5'-dFUR and newly marketed capecitabine, and, in this respect, has been presented as a determinant to fluoropyrimidine efficacy in various in vitro and in vivo models. This dual and apparently contradictory role that TP plays yields inconsistent results in the study of relationships between this enzyme expression and clinical outcome in patients treated with fluoropyrimidine analogs. Some studies have shown that high tumoral TP expression was associated indeed with poor clinical response and tumor aggressiveness. Conversely, other reports demonstrated that tumoral TP could be considered as a good response factor in patients exposed to fluoropyrimidine drugs. TP exhibits then its more favorable profile, probably in converting 5-FU to active metabolites responsible for its efficacy as antitumor agent. As a result, TP-targeting as a rationale for anticancer therapy remains unclear. TP inhibitors are being synthesized as an attempt to fight neoangiogenesis, whereas promising new strategies such as taxotere/capecitabine or radiotherapy/fluoropyrimidines associations aim at nothing but boosting TP activity to optimize drug activation in tumors. Such a discrepancy illustrates the complexity of understanding and predicting the exact role of TP in the clinical outcome of patients exposed to fluoropyrimidines, a group of major drugs extensively used in oncology.

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