Objective: Cytidine deaminase (CDD) is involved in the metabolism of new pyrimidine analogues, capecitabine (N4-pentyloxycarbonyl-5′-deoxy-5-fluorocytidine) and gemcitabine (2′,2′-difluorodeoxycytidine). The purpose of the present study was to directly examine the role of CDD in tumor cells themselves in mediating the sensitivity to capecitabine compared with gemcitabine. Methods: The human bladder cancer cell line T24 was transfected with human CDD2 cDNA by the lipofectin method. Results: Transfection of CDD2 cDNA did not change the levels of thymidine phosphorylase, dihydropyrimidine dehydrogenase and thymidylate synthase (TS) but increased the CDD activity significantly (p < 0.01). Forced expression of CDD made T24 sensitive to 5′-deoxy-5-fluorocytidine (5′DFCR) in vitro and capecitabine in vivo, but resistant to gemcitabine both in vitro and in vivo. Tetrahydrouridine, a specific CDD inhibitor, abrogated the changes in the in vitro sensitivity to 5′DFCR and gemcitabine by transfection of CDD2 cDNA. Transfection of CDD2 cDNA resulted in a significant increase in cellular 5-fluorouracil level (p < 0.01) and inhibition of TS activity (p < 0.01) after treatment with 5′DFCR in vitro. Conclusions: The present study clearly showed direct evidence for the contribution of CDD in tumor cells themselves to the sensitivities to capecitabine and gemcitabine.
Objective: To evaluate the usefulness of measuring serum CEA, CA19-9, and CYFRA 21-1 levels for the diagnosis and monitoring of bladder cancer. Materials and Methods: Serum levels of CEA, CA19-9, and CYFRA 21-1 were measured in 85 patients with bladder cancer. The absolute level of each marker and the positive rate were compared with the clinical stage and histological grade of the tumor. Changes of the markers were assessed in patients with or without disease progression, and the correlations between survival and positivity/negativity of these markers were also evaluated. Results: A higher serum level of CYFRA 21-1 was significantly correlated with higher tumor stage (p < 0.01) and higher grade (p < 0.05). In contrast, serum CEA and CA19-9 levels did not differ significantly among each stage and grade. The CYFRA 21-1 level increased significantly along with disease progression (from 7.33 ± 13.3 to 55.9 ± 127 ng/ml, p < 0.01). Patients who were positive for CYFRA 21-1 had significantly worse disease-specific survival (p < 0.0001, log rank test). Conclusion: Serum CYFRA 21-1 seems to be a marker of advanced- and high-grade urothelial carcinoma of the bladder. It is useful for monitoring this disease and for predicting the prognosis. In contrast, the clinical usefulness of CEA and CA19-9 as tumor markers was not demonstrated.
The purpose of the present study was to examine directly the role of thymidine phosphorylase (TP) in the sensitivity of renal cell carcinoma (RCC) to a novel fluoropyrimidine carbamate, capecitabine. TP cDNA-transfected RCC are used in these experiments to provide a basis for improved therapeutic benefit in chemoimmunotherapy. Human RCC line KU2 cells were transfected with pcDNA3.1/zeo(؉) with or without human TP cDNA by the lipofectin method. We established a clone transfected with pcDNA3.1/zeo(؉)/TP (KU2-TP15) and a clone transfected with pcDNA3.1/zeo(؉) as a control (KU2-C1). TP expression levels (mean ؎ SD) examined by enzyme-linked immunosorbent assay (ELISA) were 1.3 ؎ 0.14 U/mg protein in KU2, 1.6 ؎ 0.57 U/mg protein in KU2-C1 and 216 ؎ 25.6 U/mg protein in KU2-TP15. Immunohistochemical staining of subcutaneous tumors established in Balb/c nu/nu mice showed that KU2-TP15 was strongly positive for TP expression, whereas KU2 and KU2-C1 were negative. Sensitivities in vitro to 5-fluorouracil (5FU), 5-deoxy-5-fluorouridine (5DFUR) and capecitabine in KU2-TP15 were significantly enhanced compared with those in KU2 or KU2-C1. A moderate but statistically significant bystander effect was observed in vitro. KU2-TP15 tumors showed significant increase in the in vivo sensitivities to 5DFUR and capecitabine as compared with the vehicle alone while KU2-C1 tumors did not. The difference in tumor-free rate in mice bearing KU2-TP15 at 2 months after the cessation of treatment was statistically significant between the capecitabine treatment group and the controls, the 5FU treatment group and the 5DFUR treatment group. The present study clearly provides direct evidence for the role of TP in mediating the sensitivity of RCC to capecitabine. The conventional treatments with cytotoxic agents, hormones and cytokines for renal cell carcinoma (RCC) have been disappointing. 1-3 Therefore, it seems of value to explore a new regimen or a novel agent with high therapeutic index for the improvement of therapeutic efficacy against RCC. Recently, chemoimmunotherapy consisting of 5-fluorouracil (5FU) and interferon-␣ (IFN␣) with or without interleukin-2 (IL-2) has been reportedly useful in the treatment of RCC, with overall response rates of 30% to 48.6%. 4 -8 Capecitabine, a novel fluoropyrimidine carbamate, is an orally administered, tumor-selective cytotoxic agent that is converted to 5FU by three enzymes. 9 After oral administration, capecitabine is converted to 5Ј-deoxy-5-fluorocytidine (5ЈDFCR) by carboxylesterase mainly located in the liver, to 5Ј-deoxy-5-fluorouridine (5ЈDFUR) by cytidine deaminase in the liver and tumors and finally to 5FU and its active metabolites by thymidine phosphorylase (TP) in various tumors. It has been shown that TP expression or the TP/dihydropyrimidine dehydrogenase (DPD) ratio correlates well with the sensitivity to capecitabine in human cancer xenograft models, suggesting that levels of these enzymes would be a predictive factor for capecitabine. 10 The purpose of the present study was to examin...
A 68-year-old man was admitted to our hospital with left intermittent claudication. Computed tomography showed soft tissue masses surrounding the left iliac artery and in the bilateral pulmonary hilum, and the first FDG PET showed increased FDG uptake by the lesions. Retroperitoneal fibrosis associated with mediastinal fibrosis was most suspected. An open biopsy of the left peri-iliac masses revealed retroperitoneal fibrosis. Corticosteroid treatment was initiated. The second FDG PET under corticosteroid treatment showed no pathological FDG uptake. The third FDG PET after cessation of corticosteroid treatment showed increased FDG uptake in the mediastinum, and so Sairei-to treatment was initiated. The fourth FDG PET under Sairei-to treatment showed no improvement of the pathological FDG uptake, and so low-dose corticosteroid was re-started in combination with Sairei-to treatment. The fifth FDG PET under Sairei-to and corticosteroid treatment showed no pathological FDG uptake. These FDG PET findings suggest the usefulness of FDG PET for the diagnosis and monitoring of retroperitoneal fibrosis associated with mediastinal fibrosis.
Thymidine phosphorylase (TP) is a key enzyme in the activating pathway of 5'DFUR and capecitabine. On the other hand, TP is identical to platelet-derived endothelial cell growth factor (PD-ECGF) which is known to be an angiogenic factor. Recent studies show TP expression is increased in various malignancies compared with the surrounding normal tissues. These reports demonstrate that elevated TP expression indicates a predisposition for aggressive disease and/or poor prognosis. Therefore, it is a reasonable strategy to target TP in cancer treatment by using fluoropyrimidines including 5-fluorouracil (5FU), 5'DFUR and capecitabine. TP-mediated biomodulation of fluoropyrimidines to enhance their anti-tumor effects has been investigated. TP up-regulators including cytokines, anti-tumor drugs and X-ray irradiation significantly increase cytotoxicity of fluoropyrimidines. Also, transfection of TP cDNA significantly enhances cytotoxicity of fluoropyrimidines. Biomodulation of fluoropyrimidines is clinically successful in treating some malignancies. We report a review on roles of TP in biomodulation of fluoropyrimidines.
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