Abstract
Purpose
The aim of this study was to investigate the changes in two of the enzymes involved in fluorouracil metabolism, thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD), in uterine cervical squamous cell cancer tissue after radiotherapy.
Subjects and methods
Cervical tissue from 27 patients diagnosed with stage IIIB or IV uterine cervical squamous cell cancer was compared with normal cervical tissue from 33 patients with benign gynecologic diseases. Expression of TP and DPD in the cervical tissues was measured using enzyme-linked immunosorbent assays. TP and DPD expression before and after irradiation with 10 and 20 Gy was measured in 9 of the 27 patients with cervical cancer.
Results
Before irradiation, DPD expression in cancer tissue did not differ from that in normal tissue. TP expression and the TP/DPD ratio were significantly higher in cancer tissue than in normal tissue (P<0.00001). TP and DPD expression and the TP/DPD ratio were not significantly changed by irradiation with 10 and 20 Gy. TP expression and the TP/DPD ratio after irradiation with 10 and 20 Gy were significantly higher than in normal tissue.
Conclusion
The increased TP expression and the elevated TP/DPD ratio following irradiation with up to 20 Gy may offer an increased clinical advantage to chemoradiotherapy with capecitabine or doxyfluridine over radiotherapy alone.
Similar content being viewed by others
References
Rose PG, Bundy BN, Watkins EB, Thigpen JT, Deppe G, Maiman MA, Clarke-Pearson DL, Insalaco S (1999) Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 340:1144
Morris M, Eifel PJ, Lu J, Grigsby PW, Levenback C, Stevens RE, Rotman M, Gershenson DM, Mutch DG (1999) Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 340:1137
Whitney CW, Sause W, Bundy BN, Malfetano JH, Hannigan EV, Fowler WC Jr, Clarke-Pearson DL, Liao SY (1999) Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol 17:1339
Peters WA 3rd, Liu PY, Barrett RJ 2nd, Stock RJ, Monk BJ, Berek JS, Souhami L, Grigsby P, Gordon W Jr, Alberts DS (2000) Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 18:1606
Keys HM, Bundy BN, Stehman FB, Muderspach LI, Chafe WE, Suggs CL 3rd, Walker JL, Gersell D (1999) Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 340:1154
Moon Y, Todoroki T, Ohno T, Fukao K, Little JB (2000) Enhanced radiation killing by 5-fluorouracil of biliary tract cancer cell lines. Int J Oncol 16:987
Lawrence TS, Davis MA, Maybaum J (1994) Dependence of 5-fluorouracil-mediated radiosensitization on DNA-directed effects. Int J Radiat Oncol Biol Phys 29:519
Nakajima Y, Miyamoto T, Tanabe M, Watanabe I, Terasima T (1979) Enhancement of mammalian cell killing by 5-fluorouracil in combination with X-rays. Cancer Res 39:3763
Miyadera K, Sumizawa T, Haraguchi M, Yoshida H, Konstanty W, Yamada Y, Akiyama S (1995) Role of thymidine phosphorylase activity in the angiogenic effect of platelet derived endothelial cell growth factor/thymidine phosphorylase. Cancer Res 55:1687
Fox SB, Westwood M, Moghaddam A, Comley M, Turley H, Whitehouse RM, Bicknell R, Gatter KC, Harris AL (1996) The angiogenic factor platelet-derived endothelial cell growth factor/thymidine phosphorylase is up-regulated in breast cancer epithelium and endothelium. Br J Cancer 73:275
Ishikawa F, Miyazono K, Hellman U, Drexler H, Wernstedt C, Hagiwara K, Usuki K, Takaku F, Risau W, Heldin CH (1989) Identification of angiogenic activity and the cloning and expression of platelet-derived endothelial cell growth factor. Nature 338:557
Miwa M, Ura M, Nishida M, Sawada N, Ishikawa T, Mori K, Shimma N, Umeda I, Ishitsuka H (1998) Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 34:1274
Mori K, Hasegawa M, Nishida M, Toma H, Fukuda M, Kubota T, Nagasue N, Yamana H, Hirakawa YS Chung K, Ikeda T, Takasaki K, Oka M, Kameyama M, Toi M, Fujii H, Kitamura M, Murai M, Sasaki H, Ozono S, Makuuchi H, Shimada Y, Onishi Y, Aoyagi S, Mizutani K, Ogawa M, Nakao A, Kinoshita H, Tono T, Imamoto H, Nakashima Y, Manabe T (2000) Expression levels of thymidine phosphorylase and dihydropyrimidine dehydrogenase in various human tumor tissues. Int J Oncol 17:33
Hara Y (1984) 5′-Deoxy-5-fluorouridine enzymatic activation from the masked compound to 5-fluorouracil in human malignant tissues (in Japanese). Gan To Kagaku Ryoho 11:2133
Schuller J, Cassidy J, Dumont E, Roos B, Durston S, Banken L, Utoh M, Mori K, Weidekamm E, Reigner B (2000) Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. Cancer Chemother Pharmacol 45:291
Beck A, Etienne MC, Cheradame S, Fischel JL, Formento P, Renee N, Milano G (1994) A role for dihydropyrimidine dehydrogenase and thymidylate synthase in tumour sensitivity to fluorouracil. Eur J Cancer 30A:1517
Ishikawa Y, Kubota T, Otani Y, Watanabe M, Teramoto T, Kumai K, Kitajima M, Takechi T, Okabe H, Fukushima M (1999) Dihydropyrimidine dehydrogenase activity and messenger RNA level may be related to the antitumor effect of 5-fluorouracil on human tumor xenografts in nude mice. Clin Cancer Res 5:883
Nita ME, Tominaga O, Nagawa H, Tsuruo T, Muto T (1998) Dihydropyrimidine dehydrogenase but not thymidylate synthase expression is associated with resistance to 5-fluorouracil in colorectal cancer. Hepatogastroenterology 45:2117
Nishida M, Hino A, Mori K, Matsumoto T, Yoshikubo T, Ishitsuka H (1996) Preparation of anti-human thymidine phosphorylase monoclonal antibodies useful for detecting the enzyme levels in tumor tissues. Biol Pharm Bull 19:1407
US Department of Health and Human Services (1999) NCI clinical announcement. Public Health Service, National Institutes of Health, Bethesda, MD
Kono A, Hara Y, Sugata S, Karube Y, Matsushima Y, Ishitsuka H (1983) Activation of 5′-deoxy-5-fluorouridine by thymidine phosphorylase in human tumors. Chem Pharm Bull (Tokyo) 31:175
Hiroyasu S, Shiraishi M, Samura H, Tokashiki H, Shimoji H, Isa T, Muto Y (2001) Clinical relevance of the concentrations of both pyrimidine nucleoside phosphorylase (PyNPase) and dihydropyrimidine dehydrogenase (DPD) in colorectal cancer. Jpn J Clin Oncol 31:65
Sawada N, Ishikawa T, Sekiguchi F, Tanaka Y, Ishitsuka H (1999) X-ray irradiation induces thymidine phosphorylase and enhances the efficacy of capecitabine (Xeloda) in human cancer xenografts. Clin Cancer Res 5:2948
Acknowledgements
We acknowledge Nippon Roche Research Center for technical assistance with the ELISA analyses.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Oguri, H., Maeda, N., Yamamoto, Y. et al. Thymidine phosphorylase expression is preserved after radiotherapy in patients with cervical squamous cell carcinoma. Cancer Chemother Pharmacol 53, 151–154 (2004). https://doi.org/10.1007/s00280-003-0709-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00280-003-0709-6