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

Abstract

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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“…In addition, p21 overexpression was found to be associated with poor prognosis, specifically in the operable ESCC patients. Moreover, Yamashita et al [ 33 ] revealed that smoking might vary the activity of the 5-FU-related metabolic enzymes, resulting in poor curative effect. 5-Fluorouracil (5-FU) is an anticancer agent widely used in the treatment of digestive tract tumors.…”

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“…Indeed, smoking may reduce the anticancer activity of 5-FU, possibly through the induction of dihydropyrimidine dehydrogenase activity, which is the initial and rate-limiting enzyme in the catabolic pathway of 5-FU. 42 Moreover, smoking contains thousands of different compounds, which have carcinogenic activity. 43 Another interesting finding in the current study was shown in CRC patients with baseline over-expression with EGFR, in them the combination of COX2 with other cytokines expression levels generated a significant inflammation index for the prediction of DFS.…”

“…Indeed, smoking may reduce the anticancer activity of 5-FU, possibly through the induction of dihydropyrimidine dehydrogenase activity, which is the initial and rate-limiting enzyme in the catabolic pathway of 5-FU. 42 Moreover, smoking contains thousands of different compounds, which have carcinogenic activity. 43 …”

Long non-coding RNAs in Oral squamous cell carcinoma: biologic function, mechanisms and clinical implications

“…Cigarette smoke exerts inflammatory and suppressive effects on immune cells, alters mucosal immunity and promotes autoimmunity, resulting in oral cancers [10]. Yamashita et al [11] found that smoking and drinking can inhibit 5-fluorouracil (5-FU)-related metabolic enzymes through the induction of dihydropyrimidine dehydrogenase (DPD; a sole catabolic enzyme of 5-FU) activity, which in turn lead to oral cancers. In addition, alcohol consumption can interact with the polymorphisms of ALDH2 and CYP2E1-RsaI genes to increase OSCC risk [12].…”