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Activity of a Novel Anthracenyl Bishydrazone, 9,10-Anthracenedicarboxaldehyde Bis[(4,5-dihydro-1 H-imidazol-2-yl)hydrazone] Dihydrochloride, against Experimental Tumors in Mice

Departments of Chemotherapy Research [R. V. C., R. E. W., F. E. D.] and Chemical Research [K. C. M., R. B. A.] and Infectious Disease Research Section [M. F.], Medical Research Division, American Cyanamid Company, Lederle Laboratories, Pearl River, New York 10965

9,10-Anthracenedicarboxaldehyde bis[(4,5-dihydro-1 H-imidazol-2-yl)hydrazone] dihydrochloride (CL 216942; bisantrene hydrochloride; NSC 337766), a member of a new chemical class of compounds with antineoplastic properties, has been evaluated for antitumor activity in experimental murine tumor systems. The compound produced significant increases in life span (ILS) and long-term survivors among mice bearing transplantable leukemias and solid tumors. Optimal treatment regimens resulted in an ILS of >173 and 151% in mice with P388 and L1210 leukemia, respectively, an ILS of >85% in mice with Lieberman plasma cell tumor, and an ILS of >200, 150, and 63%, respectively, in mice with B16 melanoma, colon tumor 26, and Ridgway osteogenic sarcoma. An Adriamycin-resistant subline of P388 leukemia showed complete cross-resistance to CL 216942. The compound was active when administered by the i.p., i.v., and s.c. routes, but p.o. activity was not observed. Significant schedule dependency was not observed when the drug was administered once daily for 9 days, once every 4 days, or as a single dose, but single doses typically produced the best effects. CL 216942 was a potent inhibitor of DNA and RNA synthesis in L5178Y lymphoma cells cultured in vitro, and preliminary studies indicated the drug was a DNA-intercalating agent. The drug was cytotoxic for rapidly proliferating and nonproliferating (G₀) human colon carcinoma WiDR cells in vitro.

¹ To whom requests for reprints should be addressed.

Received 7/27/81. Accepted 11/ 2/81.