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Resistance Patterns between cis-Diamminedichloroplatinum(II) and Ionizing Radiation¹

Laboratory of Cancer Research and Clinical Oncology, Antwerp University, B-2610 Wilrijk, Belgium [C. M. J. D. P., P. G. S., H. J. E., J. J. H., E. E. O. G., A. T. V. O., E. A. D. B.]; Middelheim Hospital, Antwerp, Belgium [C. M. J. D. P., P. G. S.]; and TNO-MBL, Rijswijk, The Netherlands [A. M. J. F-S.]

Cross-resistance between cis-diamminedichloroplatinum(II) (CDDP) and radiation resistance has been suggested from clinical and experimental data (C. T. Coughlin and R. C. Richmond, Semin. Oncol., 16: 31–43, 1989). To determine whether cross-resistance patterns between both cytotoxic approaches exist, resistance against CDDP and ionizing radiation was induced separately in human ovarian cancer cells in a cross-over design. Subsequently sensitivity changes were determined for both treatment modalities.

CDDP resistance was induced previously (P. J. Kuppen et al., Cancer Res., 48: 3355–3359, 1988), and resistant cells were grown at three different levels of CDDP: 0 ng/ml; 250 ng/ml; and 500 ng/ml. Resistance with resistance factor (RF) 3.4 to 5.1 proved to be stable, since withdrawal of CDDP pressure for at least 6 mo did not alter resistance patterns. CDDP-resistant cells also demonstrated stable resistance against ionizing radiation, with RF ranging from 1.7 to 2.0. The resistance patterns could not be explained by differences in growth kinetics and DNA content.

Resistance to ionizing radiation was induced in the same human ovarian cancer cells as used for CDDP resistance studies. Exposure with 1.5 Gy of intermittent irradiation during 6 mo, at time intervals of 48 h, resulted in cells which were able to grow under chronic ionizing radiation pressure. RF was 2.0; the resistance was lost after 6 mo of culturing without ionizing radiation pressure. With intermittent radiation doses of 0.5 and 1.0 Gy, no significant resistance could be induced.

Cells intermittently exposed to 0.5, 1.0, and 1.5 Gy during 6 mo demonstrated increased sensitivity to CDDP, with 0.22 < RF < 0.43. Increased sensitivity was associated with proportionally increased formation of the platinum-DNA adducts. Differences in sensitivity for both ionizing radiation and CDDP were lost after 6 mo of culturing without radiation pressure; therefore, resistance toward ionizing radiation and, likewise, the increased sensitivity to CDDP, were judged to be unstable.

In conclusion, data of the present study demonstrated that development of stable resistance to CDDP is associated with development of stable resistance to ionizing radiation in human ovarian cancer. Contrastingly, increased sensitivity to CDDP was found when resistance against irradiation was induced in the same cells.

¹ Supported in part by grants from Belgian Work against Cancer (BWK), Belgian Bank ASLK, and Dr. Saal van Zwanenbergstichting.

² Recipient of Grant BWK (Belgian Work against Cancer)-10/1988. To whom requests for reprints should be addressed, at Laboratory of Cancer Research and Clinical Oncology, Antwerp University, Universiteitsplein 1 (S-4), B-2610 Wilrijk, Belgium.

Received 3/11/91. Accepted 6/25/91.

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