Induction of thymidine phosphorylase expression and enhancement of efficacy of capecitabine or 5?-deoxy-5-fluorouridine by cyclophosphamide in mammary tumor models

Abstract

Thymidine phosphorylase (dThdPase) is an essential enzyme for the activation of the oral cytostatic drugs capecitabine (N4‐pentyloxycarbonyl‐5′‐deoxy‐5‐fluorocytidine, Xeloda™) and its intermediate metabolite doxifluridine [5′‐deoxy‐5‐fluorouridine (5′‐dFUrd, Furtulon®)] to 5‐fluorouracil (5‐FUra) in tumors. In a previous study, we found that several cytostatics were able to up‐regulate tumor levels of dThdPase in a human colon cancer xenograft model. In the present study, we confirmed that the administration of cytostatics used for breast cancer treatment, such as taxanes and cyclophosphamide (CPA), up‐regulated the tumor level of dThdPase in mammary tumor models as well. Because the dThdPase up‐regulation was observed even when CPA was given orally, we investigated further the usefulness of combination therapy with the 2 oral drugs, 5′‐dFUrd/capecitabine and CPA in mammary tumor models. Daily oral administration of CPA up‐regulated human dThdPase levels in the tumor tissue of mice bearing a human mammary tumor xenograft, MX‐1, whereas in the small intestine and liver, it did not affect levels of pyrimidine nucleoside phosphorylases (PyNPase) including dThdPase and uridine phosphorylase. The preferential up‐regulation of PyNPase activity in the tumor by CPA administration was also confirmed in mice bearing a syngeneic murine mammary adenocarcinoma, A755. In both models, combination therapy of 5′‐dFUrd/capecitabine with CPA showed synergistic antitumor activity, without significant potentiation of toxicity. In contrast, treatment with CPA and either 5‐FUra or UFT (a mixture of tegafur and uracil) in combination showed only additive activity. Our results suggest that CPA and capecitabine/5′‐dFUrd, both available for oral administration, would be good partners, and that clinical trials with this drug combination against breast cancer are warranted. Int. J. Cancer 83:127–134, 1999. © 1999 Wiley‐Liss, Inc.

The role of thymidine phosphorylase, an angiogenic enzyme, in tumor progression

“…56) Furthermore, treatment of cancer patients with taxol, taxotere, cyclophosphamide, mitomycin C or X-rays increased the level of TP in tumors and synergistically enhanced the antitumor activities of prodrugs of 5-FU. [57][58][59][60] The ability of TP to enhance the activities of antitumor drugs makes it a key enzyme for combination chemotherapy of tumors. A phase II study of capecitabine and docetaxel combination chemotherapy has already started in patients with advanced gastric cancer.…”

The potential for oral combination chemotherapy of 5′-deoxy-5-fluorouridine, a 5-FU prodrug, and cyclophosphamide for metastatic breast cancer

“…In addition, mild and slow decreases in the bone marrow function allow for relatively longer intervals between monitoring examinations. Experimental researches with regard to TP upregulation, preferentially in tumour tissue by taxanes, MMC and CPA Endo et al, 1999), propose the possible potentiality of the combination therapy of these cytostatics and 5 0 -DFUR or capecitabine. 5 0 -DFUR and CPA therapy by Yoshimoto et al (1998), and capecitabine and taxotere (TXT) therapy by O' Shaughnessy et al (2002), for breast cancer showed successful clinical examples.…”

“…5 0 -DFUR and CPA therapy by Yoshimoto et al (1998), and capecitabine and taxotere (TXT) therapy by O' Shaughnessy et al (2002), for breast cancer showed successful clinical examples. Although other ideal dose settings or combination therapies using 5 0 -DFUR/capecitabine and cytostatics that exert TP up-regulation may exist, the problem remains to be seen in the optimal timing of administration of drugs in order to achieve maximum clinical effectiveness, since the process of TP upregulation in tumour tissue by particular cytostatics takes a number of (4 -6) days and TP levels gradually decrease after the discontinuation of treatment in the human cancer xenograft models Endo et al, 1999). There remain many other unresolved questions raised in this study.…”

“…Tominaga et al developed a Phase III trial comparing 5 0 -DFUR plus CPA with 5 0 -DFUR alone with the same dose setting with or without tamoxifen in an adjuvant setting, and revealed that the regimen was feasible and safe enough, causing only 4.1% of grade Z3 side effects (Tominaga et al, 2003). Experimental xenograft models, however, showed that 2-weeks rest period was too long, whereas a 1-week rest period was adequate, because the elevation of TP levels in the tumour tissue by CPA was maintained over 1 week or less (Endo et al, 1999). In this study, then, we adopted a dose setting as a daily oral combinations of 5 0 -DFUR (1200 mg/body) and CPA (100 mg/body) for 2 weeks, followed by a 1-week rest period.…”

“…Also, they demonstrated that combinations of 5 0 -DFUR/capecitabine and these cytostatics exhibited excellent synergistic activity against various human cancers in xenograft models, without significant potentiation of toxicity Endo et al, 1999). Such synergistic activities were not recognised in combination with 5-FU nor UFT (a mixture of tegaful and uracil) and these cytostatics (Endo et al, 1999). Of these cytostatics, we were particularly interested in the combination of 5 0 -DFUR and CPA as both of these drugs can be administered orally (Yoshimoto et al, 1998).…”