Effective chemoradiotherapy protocol with 5-fluorouracil for cervical squamous cell carcinoma in vitro

Purpose of investigation: 5-Fluorouracil (5FU) is frequently used in concurrent chemoradiotherapy for patients with advanced cervical cancer, although its optimal chemoradiotherapy protocol has not yet been established. In search of an optimal chemoradiotherapy protocol, some in vitro experiments were carried out.

Methods: The radiosensitive human cervical squamous cell carcinoma cell line ME180 was examined to investigate the effects of 5FU on radiosensitivity and the effects of irradiation on 5FU-sensitivity.

Results: 5FU dose-dependently enhanced cellular radiosensitivity at therapeutic concentrations. Although high doses of y-ray irradiation significantly reduced the 5FU-sensitivity, a low dose of irradiation at therapeutic doses (< 2.5 Gy) had no effect on 5FU-sensitivity of the irradiated cells. Cells pretreated with 5FU eight hours before irradiation showed significantly higher 5FU-sensitivity than cells concurrently treated with 5FU and irradiation. In contrast, cells treated with 5FU eight hours after irradiation showed significantly lower 5FU-sensitivity than cells concurrently treated with 5FU and irradiation. Moreover, all four post-irradiation surviving subclones obtained from repeatedly irradiated ME180 cells showed significantly lower 5FU-sensitivity than the non-irradiated parent cells.

Conclusion: 5FU acts as a radiosensitizer for cervical squamous cell carcinoma and 5FU-sensitivity is reduced in irradiated cells. Therefore, 5FU administration immediately before irradiation may be a more effective treatment than concurrent chemoradiotherapy or post-irradiation chemotherapy with 5FU.

5-fluorouracil; Chemoradiotherapy; Cervical cancer; Squamous cell carcinoma; Radiosensitivity; Radiosensitizer

[1] Christie D.R., Bull C.A., Gebski V., Langlands A.O.: "Concurrent 5-fluorouracil, mitomycin C and irradiation in locally advanced cervix cancer". Radio/her. Oneal., 1995, 37, 181.

[2] W hitney C.W., Sause W., Bundy B.N., Malfetano J.H., Hanmgan E.V., Fowler W.C. Jr., et al.: "Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage JIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southeast Oncology Group Study". J. Clin. Oneal., 1999, 17, 1339.

[3] Lorvidhaya V., Chitapanarux I., Sangruchi S., Lertsanguansinchai P., Kongthanarat Y., Tangkaratt S., Visetsiri E.: "Concurrent mitomycin C, 5-fluorouracil, and radiotherapy in the treatment of locally advanced carcinoma of the cervix: a randomized trial". Int. J. Rad. Oneal. Biol. Phys., 2003, 55, 1226.

[4] Tabata T., Takeshima N., Nishida H., Hirai Y., Hasumi K.: "A randomized study of primary bleomycin, vincristine, mitomycin and cisplatin (BOMP) chemotherapy followed by radiotherapy versus radiotherapy alone in stage IIIB and IVA squamous cell carcinoma of the cervix". Anticancer Res., 2003, 23, 2885.

[5] Rakovitch E., Fyles A.W., Pintilie M., Leung P.M.: "Role of mitomycin C in the development of late bowel toxicity following chemoradiation for locally advanced carcinoma of the cervix". Int J. Rad. Oneal. Biol. Phys., 1997, 38, 979.

[6] Yamamoto K., Izumi R., Hasegawa K., Nakajjima H., Ohashi K., Kubo R. et al.: "Adjuvant oral 5-fluorouracil for cervical cancer: Japanese Gynecologic Oncology Group report". Int. J. Oncol., 2004, 24, 1175.

[7] Lancillotti, F., Giandomenico, V., Affabris, E., Fiorucci, G., Romeo, G., Rossi G.B.: "Interferon alpha-2b and retinoic acid combined treatment affects proliferation and gene expression of human cervical carcinoma cells". Cancer Res., 1995, 55, 3158.

[8] Saxena A., Yashar C., Taylor D.D., Gercel-Taylor C.: "Cellular response to chemotherapy and radiation in cervical cancer". Am. J. Obstet. Gynecol., 2005, 192, 1399.