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In Vitro Toxicity and DNA Cleaving Capacity of Benzisoquinolinedione (Nafidimide; NSC 308847) in Human Leukemia¹

Departments of Hematology [B. S. A., M. Be., M. Ba.] and Chemotherapy Research [L. E. S., R. A. N., L. A. Z.], The University of Texas M. D. Anderson Hospital and Tumor Institute at Houston, Houston, Texas 77030

Benzisoquinolinedione (nafidimide; NSC 308847) is an investigational drug currently in phase I clinical testing. We have studied the antileukemic activity in vitro, the cellular drug transport, and the molecular mechanism of action with DNA of this new compound. By agarose gel electrophoresis, we verified that nafidimide is an intercalating agent, through its alteration of the electrophoretic migration of DNA products produced by the relaxing action of DNA topoisomerase I. Concentrations of up to 100 µM of nafidimide did not produce topoisomerase I-mediated DNA cleavage. Nafidimide produced DNA single-strand breaks (SSB), double-strand breaks, and DNA-protein cross-links in human myeloid leukemia cells (measured with filter elution). The ratio of SSB/DNA-protein cross-links was 1.32 ± 0.36, a value similar to that produced by 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA), suggesting that nafidimide, like m-AMSA, produced protein-associated DNA-strand breaks through a topoisomerase II-mediated reaction. The production of double-strand breaks by nafidimide also suggests the involvement of topoisomerase II in the drug-induced DNA cleavage. The cytotoxic activity of nafidimide was quantified in human myeloid leukemia cell lines differing by a factor of 70 in their cytotoxic sensitivity to m-AMSA. The m-AMSA-resistant line was less than 2-fold resistant to nafidimide. Cellular drug uptake was rapid and reached a steady state level in 30 min at 37°C. At the end of exposure, drug egress was rapid, as was the disappearance of the DNA SSB. Rapid cellular uptake of nafidimide, with low retention at the end of exposure and rapid rejoining of DNA SSB suggest that prolonged cellular exposure may be necessary for optimal antitumor effect. In vitro cloning data suggest that nafidimide may be a therapeutic option for patients with leukemia resistant to m-AMSA.

¹ Supported in part with a special fellowship grant award to B. S. A. by the Leukemia Society of America, Inc., in part by a National Cancer Institute Research Career Development Award (CA-01135) to R. A. N., and by Grant CA-40090 from the National Cancer Institute and Grant ACS-324 from the American Cancer Society (L. A. Z.).

² To whom requests for reprints should be addressed, at Department of Hematology, The University of Texas M. D. Anderson Hospital and Tumor Institute at Houston, P. O. Box 55, 6723 Bertner Avenue, Houston, TX 77030.

³ Permanent address: Internal Clinic of Medical Faculty University of Nis, Yugoslavia.

Received 1/17/86. Revised 10/ 3/86. Accepted 11/ 6/86.

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