Modulation of thymidine phosphorylase by neoadjuvant chemotherapy in primary breast cancer

Abstract

The combination effect of docetaxel and capecitabine on tumour response rate and survival was demonstrated recently in metastatic breast cancer patients. This combination was based on an experimental hypothesis that taxane can increase tumour sensitivity to the effect of capecitabine through the upregulation of thymidine phosphorylase (TP), which is responsible for the metabolism of 5-fluorouracil (5-FU) and its derivatives, including capecitabine. To examine the alteration in TP expression before and after neoadjuvant chemotherapy, 92 patients with primary breast cancer (T2-4N0-1M0) were enrolled in this study; 14 were treated with adriamycin and cyclophosphamide (AC) or epirubicin and cyclophosphamide (EC); 58 with 5-FU, adriamycin, and cyclophosphamide (FAC) or 5-FU, epirubicin, and cyclophosphamide (FEC); and 20 with FEC followed by docetaxel/taxotere (TXT-containing regimen). Thymidine phosphorylase upregulation was seen in 54.4% and 32.6% of patients in tumour cells and stromal cells, respectively. Increases in TP expression were found only in the AC/EC and TXT-containing regimen groups. In conclusion, it was strongly suggested that unlike 5-FU-containing regimens, the taxane and AC combination therapies upregulate TP expression in primary breast cancer. Thymidine phosphorylase upregulation by several anticancer drugs implies the importance of individualised strategies for sensitisation of tumour tissues to 5-FU and its derivatives.

Individually tailored treatment with epirubicin and paclitaxel with or without capecitabine as first-line chemotherapy in metastatic breast cancer: a randomized multicenter trial

“…This is supported by clinical observations of a significant relationship between response to treatment with the combination of the taxane docetaxel and capecitabine and expression of TP in tumor tissue [5]. Also anthracyclines have been reported to enhance TP upregulation [6].…”

A phase II study of capecitabine plus cisplatin in metastatic triple-negative breast cancer patients pretreated with anthracyclines and taxanes

“…26 Meanwhile, preclinical studies suggested that TP was often up-regulated by stress such as hypoxia, radiation and chemotherapy agents, 27 which included anthracyclines, taxanes, cyclophosphamide, and platinum compounds. 28 Furthermore, given the synergistic effect between cisplatin and 5-FU, 12,13 it is reasonable to expect an enhanced activity of capecitabine when administered in combination with cisplatin.…”

Antitumor activity of chemoendocrine therapy in premenopausal and postmenopausal models with human breast cancer xenografts

“…TP is upregulated in tumors by receiving stress such as hypoxia, radiation and chemotherapeutic damage. Several types of cytokines such as interleukin-1, tumor necrosis factor-α, interferon-γ also upregulate the expression of TP in malignant cells (33). Endo et al have previously reported that several types of antitumor drugs, such as taxanes, cyclophosphamide and oxaliplatin, upregulated TP in tumor tissues and that capecitabine in combination with these TP upregulators showed synergistic antitumor activity in xenograft models (32).…”