Activity of a novel anthracenedione, 1,4-dihydroxy-5,8-bis(((2-[(2-hydroxyethyl)amino]ethyl)amino])-9,10-anthracenedione dihydrochloride, against experimental tumors in mice.

1,4-Dihydroxy-5,8-bis(((2[(2-hydroxyethyl)amino]ethyl)amino))-9,-10-anthracenedione dihydrochloride (CL 232315; NSC 301739D), a representative of a new chemical class of compounds with antineoplastic properties, has been evaluated for antitumor activity in experimental mouse tumor systems. The compound produced significant increases in life span (ILS) and long-term survivors when tested against the P388 and L1210 leukemias as well as the solid neoplasms, B16 melanoma and Colon Tumor 26. The optimal treatment regimens resulted in a 173 to greater than 200% ILS with 20 to 80% 60-day survivors in mice with P388 leukemia, A 205% ILS with 55% 60-day survivors in mice with L1210 leukemia, and an ILS of greater than 300% with 80% 90-day survivors in mice with B16 melanoma. In contrast to Adriamycin, CL 232315 was active against the i.v. implanted L1210 leukemia and demonstrated moderate activity against P388/Adria, a subline of P388 resistant to Adriamycin. The compound was ineffective when tested against the Lewis lung carcinoma and the Ridgway osteogenic sarcoma. CL 232315 was active i.p., s.c., and i.v., but p.o. activity was not demonstrated. Schedule dependency was not observed when the compound was administered once daily for nine days, once every four days, or as a single dose.

Activity of a novel anthracenyl bishydrazone, 9,10-anthracenedicarboxyaldehyde Bis[(4,5-dihydro-1H-imidazol-2-yl)hydrazone] dihydrochloride, against experimental tumors in mice.

9,10-Anthracenedicarboxaldehyde bis[(4,5-dihydro-1H-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 (LS) and long-term survivors among mice bearing transplantable leukemias and solid tumors. Optimal treatment regimens resulted in an ILS of greater than 173 and 151% in mice with P388 and L1210 leukemia, respectively, an ILS of greater than 85% in mice with Lieberman plasma cell tumor, and an ILS of greater than 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 of 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.U

Antitumor agents. 1. 1,4-Bis[(aminoalkyl)amino]-9,10-anthracenediones.

The condensation of alkylenediamines with quinizarin or with 2,3-dihydro-1,4,5,8-tetrahydroxy-9,10-anthracenedione, followed by oxidation, gave 1,4-bis[aminoalkyl)amino]-9,10-anthracenediones. Some of these compounds and their 2,3-dihydro derivatives were markedly active against both leukemias and solid tumors in mice. Activity was maximal with 5,8-dihydroxylation and 1,4-bis[(2-aminoethyl)amino] substitution, in which the terminal nitrogen atoms were either unsubstituted (compound 50) or carried 2-hydroxyethyl groups (compound 40), indicating the importance of hydrophilicity. Against B-16 melanoma, 50 gave greater than 433% increase in median life span (ILS) with 7/10 80-day survivors. Against P-388 leukemia, 40 gave greater than 500% ILS with 4/5.60-day survivors; its efficacy and therapeutic index equaled or surpassed those of adriamycin, cyclophosphamide, daunorubicin, methotrexate, or 5-fluorouracil. Against L-1210 leukemia, B-16 melanoma, and colon tumor 26, 40 was generally as effective or more effective than adriamycin and is now undergoing preclinical toxicological evaluation.

Synthesis of 3,6-bis(aminoalkoxy)acridines and their effect on the immune System.

A series of 3,6-bis(aminoalkoxy)acridines (2) was prepared and shown to have a protective antiviral effect against an interferon-sensitive virus (Columbia SK) and to partially restore an antibody response to a T-cell-dependent antigen in leukemic immunosuppressed mice. The presence of circulating interferon and the stimulation of natural killer cell activity in mice was observed for 21.

Antitumor agents. 2. Bisguanylhydrazones of anthracene-9,10-dicarboxaldehydes.

9,10-Anthracenedicarboxaldehyde bis[(4,5-dihydro-1H-imidazol-2-yl)hydrazone] (bisantrene, VI-1) showed anticancer activity in mice vs. both leukemias and solid tumors. Increases in life span vs. the following neoplasms were: P-388 leukemia, 137%; B-16 melanoma, 122%; Lieberman plasma cell tumor, greater than 85%; colon tumor 26, 150%; Ridgway osteogenic sarcoma, 85%. There were significant numbers of long-term survivors. Both DNA and RNA synthesis were strongly inhibited. The drug was resistant to biodegradation and was bound strongly to tissues; in monkeys the half-life for disappearance from serum was 6 days. Related hydrazones were synthesized, and structure-activity relationships are discussed. Two routes to ring-substituted anthracene-9,10-dicarboxaldehyde intermediates were developed.