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Reduced DNA Break Formation and Cytotoxicity of the Topoisomerase II Drug 4'-(9'-Acridinylamino)methanesulfon-m-anisidide When Combined with Hyperthermia in Human and Rodent Cell Lines¹

Department of Radiobiology, University of Groningen, Bloemsingel 1, 9713 BZ, Groningen, The Netherlands

The interaction between hyperthermia and the anticancer drug 4'-(9'-acridinylamino)methanesulfon-m-anisidide (mAMSA) was studied in the human HeLa S3 and the rodent Ehrlich ascites tumor cell line. For both cell lines it was found that hyperthermia preceding the drug treatment reduced the extent of mAMSA induced DNA breakage as well as mAMSA cytotoxicity. Formation and resealing of mAMSA induced DNA break formation was found to be related to cytotoxicity. Hyperthermic protection for the action of mAMSA was found not to be a result of changed permeability for the drug. The data also do not support the possibility that heat has caused inactivation of the putative target enzyme of mAMSA, topoisomerase II. It is suggested that the hyperthermic protection for the mAMSA drug action is due to a hyperthermic alteration of the chromatin organization, especially at topoisomerase II target sequences that are found to be enriched in the nuclear matrix (P. N. Cockerill and W. T. Garrard. Cell, 44: 273–282, 1986). We show here that heat has caused an alteration of protein binding to the nucleus that seems related to the hyperthermic inhibition of mAMSA induced DNA break induction. It is concluded that preheating cells before treatment with mAMSA should not be used, at least not in this sequence, in cancer therapy.

¹ This work was supported by the Instituut voor Radiopathologie en Stralen-beschmering, The Netherlands.

Received 7/21/88. Revised 10/28/88. Accepted 1/ 3/89.