Tumoral-reduced folates and clinical resistance to fluorouracil-based treatment in head and neck cancer patients.

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Abstract
PURPOSE To describe the distribution of tumoral-reduced folates in cancer patients and to analyze the link between this parameter and antitumor efficacy of fluorouracil (FU)-based induction chemotherapy. PATIENTS AND METHODS Ninety-five patients with head and neck squamous cell carcinoma were included in the present study and 41 received induction treatment with FU-based chemotherapy (35 men and six women; mean age, 59 years; range, 40 to 76). Thymidylate synthase (TS) activity was measured according to the tritium-release assay. Reduced folates (5-10 methylenetetrahydrofolate [CH2FH4] plus tetrahydrofolate) were measured according to the entrapment assay. RESULTS Among the whole group of patients, reduced folates ranged from nondetectable (< 0.3) to 17.7 pmol/mg protein; CH2FH4 ranged from nondetectable (< 0.3) to 8.2 pmol/mg protein. There was no significant link between tumoral levels of reduced folates and the severity of disease stage. Among 41 treated patients, there were 12 (29%) complete responses (CRs), 18 (44%) partial responses (PRs), and 11 patients (27%) with no response (NR). No statistically significant relationship was observable between TS activity and response. The distribution of CH2FH4 in tumors was significantly higher for complete responders in comparison to patients with a PR or NR. CONCLUSION The present clinical data demonstrate the importance of basal tumoral-reduced folates for the achievement of optimal efficacy of FU-based treatment. They may have implications for the identification of patients resistant to FU chemotherapy and for a better understanding and management of FU modulation by folinic acid (FA).

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