Reduced Activity of Anabolizing Enzymes in 5‐Fluorouracil‐resistant Human Stomach Cancer Cells

Inaba, Makoto; Mitsuhashi, Junko; Sawada, Hiroko; Miike, Naoko; Naoe, Yoshinori; Daimon, Aiko; Koizumi, Katsuhisa; Tsujimoto, H.; Fukushima, Masakazu

doi:10.1111/j.1349-7006.1996.tb03161.x

Cited by 58 publications

(41 citation statements)

References 18 publications

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“…This data was concordant with in vitro and in vivo studies using a human gastric cancer cell line exposed to 5-FU. [35][36][37] Oxo decreased the levels of FUMP and 5-FU incorporated into RNA (F-RNA) by 70% only in the small intestine, while the decrease is limited to 0-20% in bone marrow and tumor regions in animal models. 38 Oxo is distributed at high levels in the digestive tract after oral administration, and thus reduces 5-FU-induced gastrointestinal toxicity, such as diarrhea, without affecting the antitumor activity of 5-FU.…”

Section: Discussionmentioning

confidence: 99%

Simple combinations of 5‐FU pathway genes predict the outcome of metastatic gastric cancer patients treated by S‐1

Ichikawa

Takahashi

Suto

et al. 2006

Intl Journal of Cancer

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We evaluated the expression of 5-FU pathway genes in prechemotherapeutic fresh frozen samples obtained from primary tumors to predict response and survival of 59 metastatic gastric cancer patients treated with S-1 monotherapy as first line treatment. Five 5-FU pathway genes, including thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT), thymidine phosphorylase (TP) and uridine phosphorylase (UP), were analyzed by the quantitative real-time reverse transcriptional PCR method. Median values of each gene were selected for cut-off values separating high and low gene expressions. In univariate analyses, low TS, high OPRT and low TP were significantly associated with a tumor shrinkage and a long survival, whereas DPD and UP gene expressions did not correlate with response and survival. Multivariate analyses revealed that independent variables were OPRT and TS for response and TS and TP for survival. When OPRT and TS were combined, a significantly increased accuracy rate of 91.5% was seen for response. Similarly, an increased hazard ratio of 10.29 was observed for survival in patients possessing low TS and low TP, compared with those with high TS or high TP. The simple combinations of 2 genes, OPRT and TS for response and TS and TP for survival, may allow identification of gastric cancer patients who will benefit from S-1 chemotherapy. ' 2006 Wiley-Liss, Inc.Key words: orotate phosphoribosyltransferase; thymidylate synthase; thymidine phosphorylase; dihydropyrimidine dehydrogenase; S-1 The significant survival benefit of 5-fluorouracil (5-FU)-based chemotherapy for metastatic gastric cancer compared with best supportive care is reported.1,2 5-FU combined with cisplatin has been referred to as standard chemotherapy for metastatic gastric cancer, with the median survival time ranging from 7.3 to 10.5 months.1 During the last few years, additional drugs, including oxaliplatin, taxanes, irinotecan, and oral fluoropyrimidines such as S-1, have been introduced into chemotherapy regimens for the improvement of survival. 2,3 This approach has resulted in the increase of response rate, but has not changed the median survival time under 12 months, often with a higher frequency of severe adverse events, even acceptable.1,2 Thus, there is a need for diagnostic methods that allow prediction of clinical outcome and enable a pretherapeutic discrimination of treatment effect.The antitumor effect of 5-FU is the inhibitor of thymidylate synthase (TS), an essential DNA synthetic enzyme, by 5-fluoro-2 0 -deoxyuridine-5 0 -monophosphate (FdUMP), as well as incorporation of 5-FU metabolites into RNA and DNA. 4 The initial metabolism of 5-FU into nucleotides is essential for its action by one or more of the following 3 pathways: (i) directly to 5-fluorouridine 5 0 -monophosphate (FUMP) by orotate phosphoribosyltransferase (OPRT); (ii) indirectly to FUMP in a sequence of reactions with conversion of 5-FU to 5-fluorouridine phosphorylated by uridine phosphorylase (UP); (iii) indirectly to ...

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Section: Discussionmentioning

confidence: 99%

Simple combinations of 5‐FU pathway genes predict the outcome of metastatic gastric cancer patients treated by S‐1

Ichikawa

Takahashi

Suto

et al. 2006

Intl Journal of Cancer

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“…In vitro and in vivo studies have shown that the main origin of TS-directed FdUMP metabolite comes from the reduction of FUDP by ribonucleotide reductase after prior conversion of FU to FUDP via OPRT, but not from FUdR phosphorylated by TP (Peters et al, 1986(Peters et al, , 1991Inaba et al, 1996;Koyama et al, 2000). In this study, TP negatively correlated with the antitumour effect in patients treated with a UFT and LV regimen, which agrees with previous reports on 5-FU and LV chemotherapy (Metzger et al, 1998;Salonga et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Both gene expression for orotate phosphoribosyltransferase and its ratio to dihydropyrimidine dehydrogenase influence outcome following fluoropyrimidine-based chemotherapy for metastatic colorectal cancer

et al. 2003

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Activation of 5-fluorouracil into its nucleotides requires phosphorylation by three pathways involving orotate phosphoribosyltransferase (OPRT), uridine phosphorylase (UP), or thymidine phosphorylase (TP). In this study, we investigated the association between gene expressions of these three enzymes and antitumour effect. Gene expressions in primary colorectal tumours were analysed by a real-time reverse transcriptional -polymerase chain reaction method in 37 patients receiving oral treatment of tegafururacil and leucovorin for metastatic diseases. The median values of OPRT mRNA expressions were 1.39 and 0.85 for responding tumours and nonresponding tumours, respectively, showing a statistically significant difference (P ¼ 0.0008). Responding tumours had statistically lower expressions of TP mRNA than nonresponding tumours (P ¼ 0.006). However, there was no difference in UP mRNA expression between responding and nonresponding tumours. Patients with high OPRT (X1.0) gene expression survived longer than those with low OPRT (o1.0) expression. Dihydropyrimidine dehydrogenase (DPD) gene expressions were measured. Responding tumours had a statistically higher OPRT/DPD ratio than the nonresponding ones (P ¼ 0.003). When the median value of the OPRT/DPD ratio was selected as the cutoff value, patients with a high OPRT/DPD ratio survived statistically longer than those with a low ratio (P ¼ 0.0014). In conclusion, both the expression of OPRT gene and the OPRT/DPD ratio might be useful as predictive parameters for the efficacy of fluoropyrimidine-based chemotherapy for metastatic colorectal cancer. An important anticancer agent widely used in the treatment of colorectal cancers, 5-fluorouracil (5-FU), is catabolised rapidly to the inactive metabolite dihydrofluorouracil (FUH 2 ) by the first and rate-limiting enzyme-dihydropyrimidine dehydrogenase (DPD) (Heggie et al, 1987). The main mode of action of 5-FU is thought to be through its active metabolite: 5-fluoro-uridine-5 0 -triphosphate (FUTP) or 5-fluoro-2 0 -deoxyuridine-5 0 -monophosphate (FdUMP) (Danenberg, 1977). Metabolites such as FUTP can be incorporated into RNA, while FdUMP suppresses thymidylate synthase (TS), an essential DNA de novo synthetic enzyme that catalyses the methylation of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) (Danenberg, 1977;Pinedo and Peters, 1988).With combined DPD and TS gene expressions, both response and survival could be predicted more precisely than on the bases of only one gene expression. No tumour with both high DPD and high TS expression responded to tegafur-uracil (UFT), an oral fluoropyrimidine, and leucovorin (LV) therapy, but not even all tumours with both low DPD and low TS expression responded to the therapy, such cases having a response rate of 75% (Ichikawa et al, 2003). Salonga et al (2000) reported that only one of 12 tumours with both low DPD and low TS expression was a nonresponder to 5-FU, but that case had a high thymidine phosphorylase (TP) expression. These data suggested that combined...

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“…The NUGC-3 cell line and the 5-FU-resistant NUGC-3 variant cell line, NUGC-3/5FU, were described previously. 16,17) The AGS 18) cell line was purchased from the American Type Culture Collection (ATCC). HSC-42 19,20) and KWS-1 21) cells were generously provided by Dr. Masahiko Nishiyama, Hiroshima University, and Dr. Teiichi Motoyama, Yamagata University School of Medicine, respectively.…”

Section: Methodsmentioning

confidence: 99%

Identification of candidate predictive markers of anticancer drug sensitivity using a panel of human cancer cell lines

et al. 2003

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We previously investigated the correlations between the expression of 9216 genes and various chemosensitivities in a panel of 39 human cancer cell lines 1) and found that the expression levels of AKR1B1 and CTSH were correlated with sensitivity and resistance to multiple drugs, respectively. To validate these correlations, we investigated the expression of these two genes and the chemosensitivities in 12 additional gastric cancer cell lines. The expression of AKR1B1 in the additional cell lines exhibited significant correlations with sensitivities to 8 of the 23 drugs examined, while that of CTSH displayed a significant negative correlation with only one (MS-247) of the 27 drugs examined. Their expressions were weakly correlated with sensitivity and resistance, respectively, to the remainder of the drugs. Moreover, when the 12 cell lines were divided into high-expressing and low-expressing groups, a comparison of these groups using Mann-Whitney's U test revealed that high expression levels of AKR1B1 and CTSH were related to sensitivity to 21 of the drugs and resistance to 8 of the drugs, respectively. The present results suggest that AKR1B1 and CTSH may be good markers for prediction of sensitivity to certain drugs and that our panel of 39 cell lines has the potential to identify candidate predictive marker genes. (Cancer Sci 2003; 94: 1074-1082)

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Reduced Activity of Anabolizing Enzymes in 5‐Fluorouracil‐resistant Human Stomach Cancer Cells

Cited by 58 publications

References 18 publications

Simple combinations of 5‐FU pathway genes predict the outcome of metastatic gastric cancer patients treated by S‐1

Simple combinations of 5‐FU pathway genes predict the outcome of metastatic gastric cancer patients treated by S‐1

Both gene expression for orotate phosphoribosyltransferase and its ratio to dihydropyrimidine dehydrogenase influence outcome following fluoropyrimidine-based chemotherapy for metastatic colorectal cancer

Identification of candidate predictive markers of anticancer drug sensitivity using a panel of human cancer cell lines

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