Int. J. Radiation Oncology Biol. Phys.. Vol. 34. No. 2. pp. 367-374, 1996 Copyright 0 1996 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/96 $15.00 + .OO 0360-3016( 95) 02088-S l Biology Original Contribution EFFECT OF CISPLATIN ON THE CLINICALLY RELEVANT RADIOSENSITIVITY OF HUMAN CERVICAL CARCINOMA CELL LINES RICHARD A. BRI'ITEN, PH .D.*,$ ANDREW J. EVANS, M.D., t M. JOAN ALLALUNIS-TURNER, FH .D., *'*ANDROBERT G. PEARCEY, M.D.‘$ *Department of Experimental Oncology, ‘Department of Radiation Oncology, Cross Cancer Institute, Edmonton, Alberta, T6G 122, Canada, and +Department of Oncology, University of Alberta, Edmonton, Alberta, Canada Purpose: To evaluate the effect of clinically relevant levels of cisplatin on the radiosensitivity of human cervical tumor cells, and to estimate what changes in local control rates might be expected to accrue from the concomitant use of cisplatin during fractionated radiotherapy. Methods and Materials: The effects of concomitant cisplatin (1 pg/ml, a typical intratumor concentration) on the clinically relevant radiosensitivity, i.e., surviving fraction after 2 G ( SF2) values, was determined in 19 cloned human cervical tumor cell lines. These early passage cell lines had SF2 values ranging from 0.26 to 0.87. Results: The concomitant administration of cisplatin reduced the clinically relevant radiosensitivity in the majority (11 out of 19) of the human tumor cell lines investigated. In only 4 out of 19 was any radiosensitiza- tion observed, and in 4 out of 19 cell lines there was no significant change in radiosensitivity. However, the sum of the independent cell killing by radiation and cisplatin, was approximately twofold higher than after radiation alone. There was no apparent dependence of the cisplatin-induced changes in SF, values upon the level of cell killing by cisplatin. However, there is a suggestion that concomitant cisplatin administration may have a differential effect in inherently radiosensitive and resistant human tumor cell Lines. Conclusions: Our data suggest that concomitant cisplatinkadiotherapy regimens may result in a higher level of local tumor control, but primarily through additive toxicity and not through radiosensitization. Future improvements in local tumor control may, thus, be derived by increasing the total dose of cisplatin. Radiation, Cisplatin, Cervix, Human cell lines. INTRODUCTION has been one of the agents most frequently used in chem- oradiation of cervical cancer ( 10, 30). Radiotherapy is the treatment of choice for patients with Neo-adjuvant cisplatin-containing chemotherapy re- locally advanced carcinoma of the cervix. However, 5- gimes do not result in improvement in survival (8, 32)) year survival rates of patients with International Federa- and in some trials reduced survival rates have been re- tion of Gynecology and Obstetrics (FIGO) Stage III dis- ported (29). It is not clear why these chemoradiation ease are at best 45% (24). The major cause of treatment protocols have not resulted in a net benefit. In some cases, failure in these patients is the lack of local tumor control patients have refused to complete treatment after experi- (24). In an attempt to increase local control rates, chemo- encing chemotherapy-induced toxicity (29). Another therapeutic agents are being increasingly incorporated into treatment protocols for cancer of the cervix, either possibility is that cisplatin and radiation are only effective given prior to (neo-adjuvantly), or with (concomitant) against the same tumor subpopulations, i.e., they do not radiotherapy. Cisplatin has proved to be the most active have independent levels of cell killing. The evidence to single chemotherapeutic agent in cervical cancer, with suggest that human tumor cells are differentially sensitive to radiation and cisplatin is rare; however, one recent response rates reported to be greater than 25% (2)) and study on 10 human experimental cell lines does suggest Reprint requests to: Richard A. B&ten, Ph.D., Radiobiology Program, Cross Cancer Institute, 11560 University Avenue, Ed- monton, Alberta, T6G 122, Canada. Acknowledgements-This work was funded by a grant to Dr. Richard A. Britten from the Alberta Cancer Foundation. Dr. Andrew J. Evans was the recipient of a Fellowshipfrom the Canadian CancerSociety. We thank Linda Wilson for her help in the preparation of the manuscript. Acceptedfor publication 3 August 1995. 367