Correlation between chemosensitivity and mRNA expression level of 5-fluorouracil-related metabolic enzymes during liver metastasis of colorectal cancer

Okumura, Kenji; Shiomi, Hiroya; Mekata, Eiji; Kaizuka, Machiko; Endo, Yuichi; Kurumi, Yoshimasa; Tani, Tohru

doi:10.3892/or.15.4.875

Cited by 22 publications

(24 citation statements)

References 22 publications

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“…Although these investigations have previously been reported (16)(17)(18)(19)26,27), the results remain controversial. This discrepancy may be caused by the difference in methodology and study population.…”

Section: Synchronous Liver Metastasis (N=15) Metachronous Liver Metasmentioning

confidence: 56%

“…This discrepancy may be caused by the difference in methodology and study population. As for TS mRNA expression, almost all reports have demonstrated supportive results that there was not a significant alteration between primary tumor and liver metastatic tumor (17,19,26,27), while it has been reported that the TS mRNA levels in metachronous liver metastases were higher than those in primary tumors (18). This evidence led us to the conclusion that examining the TS mRNA level in primary colorectal cancer tissue as a predictive indicator of chemosensitivity is sufficient and it is not necessary to know the TS mRNA level in liver metastatic cancer tissue.…”

Section: Synchronous Liver Metastasis (N=15) Metachronous Liver Metasmentioning

confidence: 83%

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Thymidylate synthase and thymidine phosphorylase mRNA expression in primary lesions using laser capture microdissection is useful for prediction of the efficacy of FOLFOX treatment in colorectal cancer patients with liver metastasis

et al. 2012

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Abstract. Chemotherapy with FOLFOX, which is a combination of 5-fluorouracil (5-FU)/leucovorin (LV) and oxaliplatin, has been used worldwide for the treatment of metastatic colorectal cancer patients. The aim of this study was to examine the candidates for predictors of the efficacy of the FOLFOX treatment regimen in colorectal cancer patients with liver metastasis, using formalin-fixed paraffin-embedded specimens. We investigated the mRNA levels of thymidylate synthase (TS), thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT) and excision repair cross-complementing 1 (ERCC1) in 70 primary lesions and 30 liver metastatic lesions of colorectal cancer patients, using laser capture microdissection and real-time PCR methods. We then analyzed the correlation between their expression in primary lesions and those in corresponding liver metastatic lesions (n=30) and the relationship between their expression in the primary lesions and the efficacy of mFOLFOX6 in 45 colorectal cancer patients with unresectable liver metastasis. The gene expression in primary lesions positively correlated with those in corresponding liver metastatic lesions. The profiles of gene expression of primary lesions strongly correlated with those of synchronous liver metastatic lesions compared to that of metachronous liver metastatic lesions. TS and TP mRNA levels in the patients with complete response, partial response or stable disease (n=34) were significantly lower compared to those in the patients with progressive disease (n=11) (p=0.017 and p=0.04, respectively). Our results indicated that TS and TP mRNA expression profiles in primary lesions are sufficient to estimate the mRNA expression profiles in synchronous liver metastatic lesions compared to metachronous liver metastatic lesions. Additionally, these profiles may be useful predictors in the identification of eligible colorectal cancer patients with liver metastasis for FOLFOX treatment.

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Section: Synchronous Liver Metastasis (N=15) Metachronous Liver Metasmentioning

confidence: 56%

Section: Synchronous Liver Metastasis (N=15) Metachronous Liver Metasmentioning

confidence: 83%

Thymidylate synthase and thymidine phosphorylase mRNA expression in primary lesions using laser capture microdissection is useful for prediction of the efficacy of FOLFOX treatment in colorectal cancer patients with liver metastasis

et al. 2012

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“…Our data suggest a possible mechanism of initial low passage AT-MSC chemoresistance by the expression of DPD that contributed to 5FU catabolism [28]. TP expression in AT-MSC in combination with DPD has been ascribed to 5FU resistance [29].…”

Section: Discussionmentioning

confidence: 94%

“…Cells did not exhibit any morphological changes and were found not to be tumourigenic upon subcutaneous injection in nude mice (data not shown). The expression analysis of enzymes involved in 5FU metabolism and resistance [27,28] revealed that both low passage and high passage AT-MSC express thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidylate phosphorylase (TP), orotate phosphoribosyltransferase (OPRT) ( Figure 3A). However, expression of thymidylate phosphorylase TP (plateletderived endothelial cell growth factor; PD-ECGF) was not found in human fibroblasts.…”

Section: Characterization Of Therapeutic Cells CD Y -At-mscmentioning

confidence: 99%

Cytosine deaminase expressing human mesenchymal stem cells mediated tumour regression in melanoma bearing mice

Kučerová

Matúšková

Pastorakova

et al. 2008

The Journal of Gene Medicine

163

128

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Background Previously, we validated capability of human adipose tissuederived mesenchymal stem cells (AT-MSC) to serve as cellular vehicles for gene-directed enzyme prodrug molecular chemotherapy. Yeast fusion cytosine deaminase : uracil phosphoribosyltransferase expressing AT-MSC (CD y -AT-MSC) combined with systemic 5-fluorocytosine (5FC) significantly inhibited growth of human colon cancer xenografts. We aimed to determine the cytotoxic efficiency to other tumour cells both in vitro and in vivo.

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“…Iwahashi et al reported that overall survival was significantly better in a chemosensitivity-guided chemotherapy group than in a standard chemotherapy or non-chemotherapy group in advanced gastric cancer (10). There have been several studies employing the chemosensitivity assay in ovarian cancer, breast cancer and leukemia (11)(12)(13)(14), while the number of studies using CD-DST in particular are increasing (15)(16)(17)(18)(19)(20)(21)(22)(23)(24).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the individual 50% inhibitory area under the concentration curve of 5-fluorouracil based on the collagen gel droplet embedded culture drug sensitivity test in colorectal cancer

Ochiai¹

2009

Mol Med Rep

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Abstract.We have previously reported the 5-fluorouracil (5-FU) sensitivity of cancer cells from colorectal cancer (CRC) patients using the collagen gel droplet embedded culture-drug sensitivity test (CD-DST) under multiple drug concentrations and contact durations. Moreover, the area under the concentration curve (AUC) and growth inhibition rate (IR) were combined, resulting in the AUC-IR curve, which was approximated to the logarithmic curve. In the present study, we used the AUC-IR curve to calculate the individualized AUC IR50 , the AUC value that imparts 50% growth inhibition. Individual AUC IR50 was calculated in CRC patients, and its distribution was evaluated. The cumulative distribution of individual AUC IR50 was regressed over two lines (logarithmic scale). Among the 45 resectable CRC patients, those who achieved more than the individual AUC IR50 during post-operative 5-FUbased chemotherapy demonstrated a trend towards better disease-free survival compared to those who did not achieve AUC IR50 . Of the Dukes' D patients (n=10), those who achieved more than twice the individual AUC IR50 during post-operative 5-FU-based chemotherapy demonstrated significantly better survival rates (p=0.05) than those who did not. In this study, the distribution of the individual AUC IR50 suggested that approximately 6% of patients demonstrated very low 5-FU sensitivity. Therefore, the individual AUC IR50 was useful in classifying good, intermediate and poor 5-FU response. Achievement of the individual AUC IR50 may be a prerequisite for individualized 5-FU-based adjuvant chemotherapy. As well, the early achievement of twice the individual AUC IR50 may indicate an improved prognosis in Dukes' D patients. The individual AUC IR50 using CD-DST is useful in determining the individualized chemotherapy of CRC patients, thus CD-DST has the potential to facilitate the establishment of individualized chemotherapy for CRC. IntroductionIndividualized chemotherapy is a therapeutic strategy based on the features of a respective tumor, and has been proposed to improve patient clinical outcome while maintaining quality of life. In the field of gastrointestinal cancer, 5-fluorouracil (5-FU) is the drug most often used to assess antitumor effect. The drug sensitivity of tumor cells is one of the key factors that must be assessed in individualized chemotherapy for cancer patients. We have reported the 5-FU sensitivity of cancer cells from colorectal cancer (CRC) patients using the collagen gel droplet embedded culture-drug sensitivity test (CD-DST) under multiple drug concentrations and contact durations. Moreover, the area under the concentration curve (AUC) and growth inhibition rate (IR) were combined, resulting in the AUC-IR curve, which was approximated to the logarithmic curve (1). We have also reported that the growth inhibition rate, calculated from the AUC-IR curve, and the actual growth inhibition rate, at an AUC of 48 μg x h/ml, are identical. Based on these results, we proposed that the in vitro antitumor effect of 5-FU depends o...

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Correlation between chemosensitivity and mRNA expression level of 5-fluorouracil-related metabolic enzymes during liver metastasis of colorectal cancer

Cited by 22 publications

References 22 publications

Thymidylate synthase and thymidine phosphorylase mRNA expression in primary lesions using laser capture microdissection is useful for prediction of the efficacy of FOLFOX treatment in colorectal cancer patients with liver metastasis

Thymidylate synthase and thymidine phosphorylase mRNA expression in primary lesions using laser capture microdissection is useful for prediction of the efficacy of FOLFOX treatment in colorectal cancer patients with liver metastasis

Cytosine deaminase expressing human mesenchymal stem cells mediated tumour regression in melanoma bearing mice

Evaluation of the individual 50% inhibitory area under the concentration curve of 5-fluorouracil based on the collagen gel droplet embedded culture drug sensitivity test in colorectal cancer

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