Thymidine phosphorylase and dihydropyrimidine dehydrogenase are predictive factors of therapeutic efficacy of capecitabine monotherapy for breast cancer-preliminary results

Abstract

Capecitabine monotherapy was administered for 25 patients with advanced or recurrent breast cancer, and the clinical therapeutic efficacy and its relationship to expression of 5-fluorouracil-related enzymes (i. e., thymidine phosphorylase (TP), thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD)) were investigated. The expressions of TP, TS and DPD were determined by immunohistochemical staining techniques and rated using a scoring system of 1~4. The expression score for TP/DPD showed a statistically significant correlation with the clinical response, whereas the expression score for TP/TS also showed a correlation but it was not statistically significant. The number of patients was small, but the results revealed the potential of application of the TP/DPD expression score as a factor for predicting the efficacy of the drug in individual patients.

Phase II study of 4-weekly capecitabine monotherapy in advanced/metastatic breast cancer

“…In contrast, UFT (an oral fluoropyrimidine combining tegafur and uracil) showed no anti-tumor activity in the majority of 5-FU-resistant cell lines. Susceptibility of xenograft models to capecitabine correlates with the ratio of tumoral thymidine phosphorylase to dihydropyrimidine dehydrogenase [17,18], but such a correlation is not seen with UFT [17]. Therefore, it is possible that the activity of capecitabine in 5-FU-resistant tumors may relate to generation of 5-FU preferentially in tumor tissue, where thymidine phosphorylase concentrations are significantly higher than in non-tumor tissue [18].…”

“…Susceptibility of xenograft models to capecitabine correlates with the ratio of tumoral thymidine phosphorylase to dihydropyrimidine dehydrogenase [17,18], but such a correlation is not seen with UFT [17]. Therefore, it is possible that the activity of capecitabine in 5-FU-resistant tumors may relate to generation of 5-FU preferentially in tumor tissue, where thymidine phosphorylase concentrations are significantly higher than in non-tumor tissue [18]. Of note, in the clinical setting others have reported activity of capecitabine in patients previously exposed to 5-FU [18].…”

“…Therefore, it is possible that the activity of capecitabine in 5-FU-resistant tumors may relate to generation of 5-FU preferentially in tumor tissue, where thymidine phosphorylase concentrations are significantly higher than in non-tumor tissue [18]. Of note, in the clinical setting others have reported activity of capecitabine in patients previously exposed to 5-FU [18]. These prelinical and clinical findings are relevant to current and future clinical practice, as recent data have shown that the addition of capecitabine to adjuvant anthracycline-and taxane-containing regimens significantly Prothrombin time prolongation 5 (10) 1 (2) --6 (12)…”

Prognostic impact of dihydropyrimidine dehydrogenase expression on pancreatic adenocarcinoma patients treated with S‐1‐based adjuvant chemotherapy after surgical resection

“…Several clinical studies on gastrointestinal and other cancers that have been largely treated with 5-FU-based chemotherapy have demonstrated that variation of expression of intratumoral enzymes involved in the metabolism of 5-FU and its derivatives (such as TS, DPD, and OPRT) is associated with efficacy and/or patient prognosis [21,[25][26][27][28][29]. However, only a few reports have demonstrated a relationship between TS, DPD, and OPRT expression and the outcome of pancreatic carcinoma patients treated with fluoropyrimidines [22,30,31], and no reports about such associations in pancreatic carcinoma patients treated with S-1 after surgical resection have been published.…”

Impact of prophylactic pyridoxine on occurrence of hand–foot syndrome in patients receiving capecitabine for advanced or metastatic breast cancer

“…In another study, patients developing HFS during capecitabine therapy showed a trend towards increased intratumoral concentrations of TP and reduced intratumoral concentrations of dihydropyrimidine dehydrogenase (DPD) (and thus an increased TP-to-DPD ratio) compared with patients who did not experience HFS [23]. TP-to-DPD ratio also correlates with capecitabine efficacy [24]. Therefore, the apparent correlation between clinical efficacy and HFS may result from the relationship of both of these outcomes with the TP-to-DPD ratio.…”