No 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.

To screen for glycoproteins showing aberrant sialylation patterns in sera of cancer patients and apply such information for biomarker identification, we performed SELDI-TOF MS analysis coupled with lectin-coupled ProteinChip arrays (Jacalin or SNA) using sera obtained from lung cancer patients and control individuals. Our approach consisted of three processes (i) removal of 14 abundant proteins in serum, (ii) enrichment of glycoproteins with lectin-coupled ProteinChip arrays, and (iii) SELDI-TOF MS analysis with acidic glycoprotein-compatible matrix. We identified 41 protein peaks showing significant differences (p<0.05) in the peak levels between the cancer and control groups using the Jacalin- and SNA-ProteinChips. Among them, we identified loss of Neu5Ac (alpha2,6) Gal/GalNAc structure in apolipoprotein C-III (apoC-III) in cancer patients through subsequent MALDI-QIT-TOF MS/MS. Furthermore, subsequent validation experiments using an additional set of 60 lung adenocarcinoma patients and 30 normal controls demonstrated that there is a higher frequency of serum apoC-III with loss of alpha2,6-linkage Neu5Ac residues in lung cancer patients compared to controls. Our results have demonstrated that lectin-coupled ProteinChip technology allows the high-throughput and specific recognition of cancer-associated aberrant glycosylations, and implied a possibility of its applicability to studies on other diseases.

Capecitabine (N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) is a novel fluoropyrimidine carbamate that was synthesized for the purpose of finding antitumor drugs with improved safety and efficacy profiles compared with those of 5-fluorouracil (5-FUra) and doxifluridine (5'-deoxy-5-fluorouridine, 5'-dFUrd). The present study compared the antitumor activities of the compound with those of other fluoropyrimidines in 12 human cancer xenograft models and their antimetastatic activities in murine tumor models. The antitumor efficacy of capecitabine was greater than those of 5'-dFUrd, UFT (a mixture of tegafur and uracil) and 5-FUra. Capecitabine was also much safer, particularly much less toxic to the intestinal tract, than the other compounds, indicating higher therapeutic indices. The therapeutic indices of capecitabine, 5'-dFUrd and 5-FUra were >40, >20 and 2.0 against the human CXF280 colon cancer xenograft, the most sensitive line to the fluoropyrimidines so far tested, and 5.1, 1.5, and <1.5 against the human HCT116 colon cancer xenograft with ordinary sensitivity, respectively. In addition, capecitabine, as well as 5'-dFUrd, selectively suppressed the spontaneous metastasis of mouse Lewis lung carcinoma in mice at extremely low doses, 32-64 fold lower than their minimum effective dose (MED) against the primary tumor growth. Capecitabine was even more antimetastatic than 5'-dFUrd. These results indicate that capecitabine has high therapeutic potential.