Dihydropyrimidine dehydrogenase expression predicts survival outcome and chemosensitivity to 5-fluorouracil in patients with oral squamous cell carcinoma

Kobayashi, H; Koike, Takeshi; Nakatsuka, Atsushi; Kitamura, Hiroshi; Sagara, Junji; Taniguchi, Shun’ichiro; Kurashina, Kenji

doi:10.1016/j.oraloncology.2004.06.003

Cited by 24 publications

(31 citation statements)

References 23 publications

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“…1). Thus, the anticancer effects of 5-FU are closely correlated with the activity of its metabolic enzymes, which have been extensively investigated in oral cancers (3,4,8,9,11,16).…”

Section: Discussionmentioning

confidence: 99%

“…DPD is the initial and rate-limiting enzyme that catabolizes 5-FU in the liver. Therefore, DPD in tumor cells may reduce the anticancer effects of 5-FU and several studies reported that the levels of DPD expression are significantly correlated with resistance to 5-FU (8)(9)(10)17). Lifestyle habits, including cigarette smoking and alcohol consumption, are known to affect drug treatment through pharmacokinetic and pharmacodynamic mechanisms (19)(20)(21)23).…”

Section: Discussionmentioning

confidence: 99%

“…The effects of 5-FU are closely associated with the activity of its metabolic enzymes. The 5-FU-related enzymes, namely thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyl transferase (OPRT) and thymidine phosphorylase (TP), play a significant role in the anticancer effects of 5-FU (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). Therefore, evaluation of the mRNA expression levels of these enzymes may determine the desirable efficiency and concomitant side effects of 5-FU.…”

Section: -Fluorouracil (5-fu)mentioning

confidence: 99%

“…From this point of view, the correlation between enzyme expression and anticancer effects has been extensively investigated (3,4,8,9,11,16). Although there are controversial points, it was suggested that the high expression of DPD in tumor tissues may reduce the anticancer effects of 5-FU (8)(9)(10)17).…”

Section: -Fluorouracil (5-fu)mentioning

confidence: 99%

“…Therefore, evaluation of the mRNA expression levels of these enzymes may determine the desirable efficiency and concomitant side effects of 5-FU. From this point of view, the correlation between enzyme expression and anticancer effects has been extensively investigated (3,4,8,9,11,16). Although there are controversial points, it was suggested that the high expression of DPD in tumor tissues may reduce the anticancer effects of 17).…”

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confidence: 99%

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Effects of smoking and alcohol consumption on 5-fluorouracil-related metabolic enzymes in oral squamous cell carcinoma

Yamashita

Kato

Long

et al. 2014

Molecular and Clinical Oncology

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Abstract. Lifestyle, particularly smoking and alcohol consumption, may induce and/or inhibit drug metabolism. In order to reveal the effects of smoking and alcohol consumption on the 5-fluorouracil (5-FU)-related metabolic enzymes, namely thymidylate synthase, dihydropyrimidine dehydrogenase (DPD; a sole catabolic enzyme of 5-FU), orotate phosphoribosyl transferase (OPRT) and thymidine phosphorylase, in oral squamous cell carcinomas, the mRNA expression of these enzymes was investigated in 29 surgical specimens and compared by the Brinkman index and drinking years. The surgical specimens were divided into normal and tumor regions and were independently analyzed using quantitative reverse transcription-polymerase chain reaction. There was a significantly positive correlation between DPD mRNA expression in these tissues and Brinkman index̸drinking years, with OPRT mRNA expression being significantly correlated to the Brinkman index in tumor tissues. These results revealed that lifestyle habits, including smoking and alcohol consumption, may vary the activity of the 5-FU-related metabolic enzymes. DPD is the initial and rate-limiting enzyme in the catabolic pathway of 5-FU. Therefore, smoking and alcohol consumption may reduce the anticancer activity of 5-FU, possibly through the induction of DPD activity.Introduction 5-Fluorouracil (5-FU) is an anticancer agent widely used in the treatment of several types of cancer, including gastrointestinal, mammary, head and neck, non-small-cell lung and oral cancers. The effects of 5-FU are closely associated with the activity of its metabolic enzymes. The 5-FU-related enzymes, namely thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyl transferase (OPRT) and thymidine phosphorylase (TP), play a significant role in the anticancer effects of 5-FU (1-15). Therefore, evaluation of the mRNA expression levels of these enzymes may determine the desirable efficiency and concomitant side effects of 5-FU. From this point of view, the correlation between enzyme expression and anticancer effects has been extensively investigated (3,4,8,9,11,16). Although there are controversial points, it was suggested that the high expression of DPD in tumor tissues may reduce the anticancer effects of 17).Cigarette smoking is a major risk factor for the development of squamous cell carcinoma of the head and neck. Additionally, alcohol consumption has long been known as a risk factor for head and neck cancers (18). Previous evidence indicates that patients with head and neck cancers, including oral cancers, are highly likely to lead such lifestyles. Furthermore, it was reported that lifestyle, particularly smoking and/or alcohol consumption, may modulate drug metabolism through enzyme induction and/or inhibition (19-21). However, there is currently no available report regarding the effects of these lifestyle habits on the status of 5-FU-related metabolic enzymes. In the present study, in order to elucidate the effects of smoking and alcohol consumption on the 5-FU-re...

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“…1). Thus, the anticancer effects of 5-FU are closely correlated with the activity of its metabolic enzymes, which have been extensively investigated in oral cancers (3,4,8,9,11,16).…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: -Fluorouracil (5-fu)mentioning

confidence: 99%

Section: -Fluorouracil (5-fu)mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Effects of smoking and alcohol consumption on 5-fluorouracil-related metabolic enzymes in oral squamous cell carcinoma

Yamashita

Kato

Long

et al. 2014

Molecular and Clinical Oncology

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Genetic determinants for activated fluoropyrimidine chemotherapy

Gmeiner

2006

Drug Development Research

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Fluoropyrimidines (FPs) remain widely used for the treatment of diverse malignancies more than four decades following the initial report of 5-fluorouracil (5FU), the archetypal FP, as a novel compound with potential anti-neoplastic activity. Subsequent decades of research have enriched our understanding of the biochemical mechanisms that are important for FP activation as well as the genetic determinants that are predictive of the likely success, or failure, of FP chemotherapy for a particular individual. The concept that chemotherapy should be customized to complement the genetic profiles of cancer patients has become increasingly important as genotyping of tumor samples has become possible and as the number of available anticancer drugs has increased. Significant progress has been made in identifying the gene expression profiles for cancer patients who are likely to benefit from treatment with FPs. In this review, we will summarize the results of retrospective clinical studies correlating response to FP chemotherapy with the expression of specific genes, such as TS and DPD. We will also present a summary of FPs in current clinical use, including orally bioavailable FPs such as capecitabine, as well as FPs that are in pre-clinical development, such as FdUMP [10]. Refinement of a target population through pharmacogenetic analysis and development of novel FPs that evoke very high response rates in this target population will likely result in the use of FP regimens in the coming era when cancer becomes a largely manageable disease. Drug Dev.

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Relative level of thymidylate synthase mRNA expression in primary tumors and normal tissues predicts survival of patients with oral tongue squamous cell carcinoma

Yasumatsu

Nakashima

Wakasaki

et al. 2009

Eur Arch Otorhinolaryngol

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Thymidylate synthase (TS) is a major target of 5-fluorouracil (5-FU) and dihydropyrimidine dehydrogenase (DPD) is a rate-limiting enzyme in the degradation of 5-FU. There are no studies investigating the comparison of TS and DPD mRNA expressions in oral tongue SCC (OSCC) and nontumor tissues obtained from the same patients. In addition, increased interest has been focused on the biological roles of TS and DPD as the independent prognostic factors as well as responsive determinants for cancer patients with 5-FU based therapy. We determined the expression levels of TS and DPD in tumor (T) and nontumor squamous epithelial tissues (N) of OSCC using real-time reverse transcription-polymerase chain reaction and evaluated whether the T/N ratio would correlate with clinicopathological factors. The mRNA expressions of TS and DPD were significantly higher in tumor areas than in nontumor areas. No correlation was found between the T/N ratio of each mRNA expression and gender, clinical stage, T classification, N classification or differentiation. The T/N ratio of TS in patients that died of disease was significantly higher than in patients with free of disease, whereas there were no relationships between The T/N ratio of DPD and disease status. Clinical follow-up data showed shorter overall survival periods for cases with high T/N ratio of TS than for cases with low T/N ratio of TS with the statistically significant. Our study showed that TS but not DPD seems to have prognostic value in OSCC. These findings suggest that the assessment of TS activity may be useful both in the management and in the treatment of OSCC.

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Dihydropyrimidine dehydrogenase expression predicts survival outcome and chemosensitivity to 5-fluorouracil in patients with oral squamous cell carcinoma

Cited by 24 publications

References 23 publications

Effects of smoking and alcohol consumption on 5-fluorouracil-related metabolic enzymes in oral squamous cell carcinoma

Effects of smoking and alcohol consumption on 5-fluorouracil-related metabolic enzymes in oral squamous cell carcinoma

Genetic determinants for activated fluoropyrimidine chemotherapy

Relative level of thymidylate synthase mRNA expression in primary tumors and normal tissues predicts survival of patients with oral tongue squamous cell carcinoma

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