Irradiation reduces bleomycin sensitivity in cervical squamous cancer cells in vitro

Purpose of investigation: The study was performed to examine how bleomycin (BLM) and peplomycin (PEM) should be effectively used in radiotherapy for cervical squamous cancer patients. Methods: The effects of BLM on radiosensitivity and the effects of radiation on the sensitivity to BLM of cancer cells were investigated using the radiosensitive human cervical squamous cell carcinoma cell line ME180. Results: BLM treatment did not affect radiosensitivity. However, irradiation significantly reduced cell BLM sensitivity in a dose-dependent manner. There was no significant difference in BLM sensitivity and PEM sensitivity between cells concurrently irradiated and those treated with BLM or PEM 8 h before or 8 h after irradiation. Conclusion: Since sensitivity to BLM is reduced during irradiation, BLM should be administered to cervical cancer patients as an adjuvant chemotherapeutic drug after completion of radiotherapy.

Bleomycin; Peplomycin; Cervical cancer; Chemoradiotherapy; Squamous cell carcinoma

[1] Morris M.. Eifel P.J., Lu J., Grigsby P.W., Levenback C., Stevens R.E. et al.: "Pelvic radiation with concurrent chemotherapy cornpared with pelvic and para-aortic radiation for high-risk cervical cancer". New Engl. J. Med., I 999, 340, 1137.

[2] Rose P.G., Bundy B.N., Watkins E.B., Thigpen J.T., Deppe G., Maiman M.A. et al.: "Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer". New Engl. J Med., 1999, 340, 1144.

[3] Keys H.M., Bundy B.N., Stehrnan F.B., Muderspach L.l., Chafe W.E., Suggs C.L. 3rd et al.: "Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky Stage IB cervical carcinoma". New Engl. J. Med., 1999, 340, 1154.

[4] Peters W.A. 3rd, Liu P.Y., Barrett R.J. 2nd, Stock R.J., Monk B.J., Berek J.S. et al.: "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., 2000, 18, 1606.

[5] Tanaka T., Yukawa K., Umesaki N.: "Radiation enhances c1splatin- sensitivity in human cervical squamous cancer cells in vitro". Eur. J. Gynaecol. Oneal., 2005, 26, 431.

[6] Tanaka T., Umesaki N.: "Radiation reduces pirarubicin sensitivity in human cervical squamous cell carcinoma cells". Oneal. Rep., 2005. 13, 1165.

[7] Tanaka T., Umesaki N.: "Effects of mitomycin C on radiationinduced cell death in human cervical squamous cell carcinomas". Eur. J. Gynaecol. Oneal., 2005, 26, 411.

[8] Lancillotti F., Gianslomenico 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 c-ells". Cancer Res:, 1995,-55, 3158.

[9] lwasaka T., Kamura T., Yokoyama M., Matsuo N., Nakano H., Sugimori H.: "Adjuvant chemotherapy after radical hysterectomy for cervical carcinoma: a comparison with effects of adjuvant radiotherapy". Obstet. Gynecol., 1998, 91, 977.

[10] Sugiyama T., Nishida T., Hasuo Y., Fujiyoshi K., Yakushiji M "Neoadjuvant intraarterial chemotherapy followed by radical hysterectomy and/or radiotherapy for locally advanced cervical cancer". Gynecol. Oneal., 1998, 69, 130.

[11] Goldhirsch A., Greiner R., Bleher A., Jeschko M., Dreher E., Krauer F., Cavalli F.: "Combination of chemotherapy with methotrexate, bleomycin, and cis-platinum, and radiation therapy for locally advanced carcinoma of the cervix". Am. J. Clin. Oneal., 1986, 9, 12.

[12] Souhami L., Gil R.A., Allan S.E., Canary P.C., Araujo C.M., Pinto L.H., Silveira T.R.: "A randomized trial of chemotherapy followed by pelvic radiation therapy in Stage IIIB carcinoma of the cervix". J. Clin. Oncol., 1991, 9, 970.

[13] Kumar L., Kaushal R., Nandy M., Biswal B.M., Kumar S., Kriplani A. et al.: "Chemotherapy followed by radiotherapy versus radiotherapy alone in locally advanced cervical cancer: a randomized study". Gynecol. Oneal,. 1994, 54, 307.

[14] Bloss J.D., Lucci J.A. 3rd, DiSaia P.J., Manetta A., Schiano M.A., Ramsinghani N., Berman M.L.: "A phase II trial of neoadjuvant chemotherapy prior to radical hysterectomy and/or radiation therapy in the management of advanced carcinoma of the uterine cervix". Gynecol. Oneal., 1995, 59, 105.

[15] Napolitano U., Imperato F., Mossa B., Framarino M.L., Marziam R., Marzetti L.: "The role of neoadjuvant chemotherapy for squamous cell cervical cancer (lb-Illb): a long-term randomized trial". Eur. J. Gynaecol. Oneal., 2003, 24, 51.

[16] Bloss J.D., Lucci J.A. 3rd, DiSaia P.J.. Manetta A., Schiano M.A., Ramsinghani N., Berman M.L.: "A phase II trial of neoadjuvant chemotherapy prior to radical hysterectomy and/or radiation therapy in the management of advanced carcinoma of the uterine cervix". Gynecol. Oneal., 1995, 59, 105.

[17] Chang T.C., Lai C.H., Hong J.H., Hsueh S., Huang K.G., Chou H.H. et al.: "Randomized trial of neoadjuvant cisplatin, vincristine, bleomycin, and radical hysterectomy versus radiation therapy for bulky Stage 1B and IIA cervical cancer". J. Clin Oneal., 2000, 18, 1740.

[18] Curtin J.P., Hoskins W.J., Venkatraman E.S., Almadrones L., Podratz K.C., Long H. et al.: "Adjuvant chemotherapy versus chemotherapy plus pelvic irradiation for high-risk cervical cancer patients after radical hysterectomy and pelvic lymphadenectomy (RH-PLND): a randomized phase III trial". Gynecol. Oncol., 1996, 61, 3.

[19] Lin J.C,. Ho E.S., Jan J.S., Yang C.H., Liu F.S.: "High complete response rate of concomitant chemoradiotherapy for locally advanced squamous cell carcinoma of the uterine cervix". Gynecol. Oncol., 1996, 61, 101.

[20] Aoki M., Akahira J., Niikura H., Saito S., Abe Y., Aida T. et al.: "Retrospective analysis of concurrent chemoradiation with the combination of bleomycin, ifosfamide and cisplatin (BIP) for uterine cervical cancer". Tohoku J. Exp. Med., 2004, 204, 309.

[21] Soeters R., Bloch B., Levin W., Dehaeck C.M., Goldberg G "Combined chemotherapy and radiotherapy in patients with advanced squamous carcinoma of the cervix (cis-platinumbleomycin- vinblastine)". Gynecol. Oncol., 1989. 33, 44.

[22] Tseng C.J., Chang C.T., Lai C.H., Soong Y.K., Hong J.H., Tang S.G., Hsueh S.: "A randomized trial of concurrent chemoradiotherapy versus radiotherapy in advanced carcinoma of the uterine cervix". Gynecol. Oncol., 1997, 66, 52.

[23] Alberts D.S., Kronmal R., Baker L.H., Stock-Novack D.L., Surwit E.A., Boutselis J.G., Hannigan E.V.: "Phase II randomized trial of cisplatin chemotherapy regimens in the treatment of recurrent or metastatic squamous cell cancer of the cervix: a Southwest Oncology Group Study". J. Clin. Oncol., 1987, 5: 1791-1795.

[24] Bloss J.D., Blessing J.A., Behrens B.C., Mannel R.S., Rader J.S., Sood A.K. et al.: "Randomized trial of cisplatin and ifosfamide with or without bleomycin in squamous carcinoma of the cervix a gynecologic oncology group study". J. Clin. Oncol., 2002, 20, 1832.

[25] Picozzi VJ. Jr, S如c B.I., Carlson R.W., Koretz M., Ballon S.C "Bleomycin, mitomycin, and cisplatin therapy for advanced squamous carcinoma of the uterine cervix: a phase II study of the Northern California Oncology Group". Cancer Treat. Rep., 1985, 69, 903.