Clement J J, Burres N, Jarvis K, Chu D T, Swiniarski J, Alder J
Abbott Laboratories, Abbott Park, Illinois 60064-3500.
Cancer Res. 1995 Feb 15;55(4):830-5.
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.
A - 84441是一种新型强效抗肿瘤喹诺酮类药物，在体外和体内对小鼠及人类肿瘤均有活性。A - 84441作为前体药物，其效力与母体化合物相当，对一组小鼠和人类肿瘤细胞系的IC50范围为0.03 - 0.49微克/毫升。母体化合物以镁依赖的方式与哺乳动物DNA结合，并抑制DNA和RNA合成。A - 84441显著延长了腹腔注射植入的三种小鼠肿瘤模型的生存期，并实现了治愈。A - 84441对九种实体瘤中的七种有活性，包括皮下小鼠肿瘤和人类肿瘤异种移植瘤。与腹腔注射相比，静脉注射该化合物时似乎更具活性。尽管多次分次给药通常比单次给药更有效，但给药方案对抗肿瘤疗效影响不大。A - 84441对小鼠白血病细胞的活性比对正常小鼠骨髓细胞高10倍以上。通过静脉或腹腔途径给药时，单次或多次给药后A - 84441的急性毒性在11至50毫克/千克之间，具体取决于给药方案。口服给药时，该药物无明显毒性或疗效。
