Biological characterization of a novel antitumor quinolone.
A-84441, a potent new antitumor quinolone, was active in vitro and in vivo against murine and human tumors. A-84441, a prodrug, was comparable in potency to the parent compound with an IC50 range of 0.03-0.49 microgram/ml against a panel of murine and human tumor cell lines. The parent compound bound mammalian DNA in a magnesium-dependent manner and caused inhibition of DNA and RNA synthesis. A-84441 produced a significant increased life span and cures in three lines of i.p. implanted murine tumors. A-84441 was active against seven of nine solid tumors including s.c. murine tumors and human tumor xenografts. The compound appeared to be more active when administered i.v. compared to i.p. injection. Antitumor efficacy was little effected by treatment schedule, although multiple divided dosing was generally more effective than single dose treatment. A-84441 was over 10-fold-more active against murine leukemic cells than against normal murine bone marrow cells. The acute toxicity of A-84441 following single or multiple dosing ranged between 11 and 50 mg/kg dependent on schedule of administration when given by i.v. or i.p. route. The agent had no apparent toxicity or efficacy when administered p.o.
Clement
J J
JJ
Abbott Laboratories, Abbott Park, Illinois 60064-3500.
Burres
N
N
Jarvis
K
K
Chu
D T
DT
Swiniarski
J
J
Alder
J
J
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D001853:Bone Marrow / Q000187:drug effects; D004273:DNA, Neoplasm / Q000378:metabolism; D004334:Drug Administration Schedule; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007928:Lethal Dose 50; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy; D009374:Neoplasms, Experimental / Q000188:drug therapy; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D015363:Quinolones / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000187:drug effects
C091970:A 84441; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D011355:Prodrugs; D015363:Quinolones