Geroni C, Ripamonti M, Arrigoni C, Fiorentini F, Capolongo L, Moneta D, Marchini S, Della Torre P, Albanese C, Lamparelli M G, Ciomei M, Rossi R, Caruso M
Department of Pharmacology, Pharmacia Corporation, Milan, Italy.
Cancer Res. 2001 Mar 1;61(5):1983-90.
4-demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulphonyl-daunorubicin (PNU-159548) belongs to a novel class of antitumor compounds (termed alkycyclines) and is currently undergoing Phase II clinical trial. In the present study, we investigated the in vitro and in vivo antitumor activity, the pharmacokinetics, and the toxicological profile of this compound. PNU-159548 showed good cytotoxic activity in murine and human cancer cells growing in vitro, with an average concentration for 50% growth inhibition of 15.8 ng/ml. The drug showed strong antitumor efficacy in vivo after i.v. and p.o. administration against rapidly proliferating murine leukemias and slowly growing transplantable human xenografts. At non-toxic doses, PNU-159548 produced complete regression and cures in ovarian, breast, and human small cell lung carcinomas. Fourteen of 16 models studied, including colon, pancreatic, gastric, and renal carcinomas, astrocytoma and melanoma, were found to be sensitive to PNU-159548. In addition, PNU-159548 was effective against intracranially implanted tumors. Toxicological studies revealed myelosuppression as the main toxicity in both mice and dogs. The maximum tolerated doses, after a single administration, were 2.5 mg/kg of body weight in mice, 1.6 mg/kg in rats, and 0.3 mg/kg in dogs. In the cyclic studies, the maximum tolerated doses were 0.18 mg/kg/day (cumulative dose/cycle: 0.54 mg/kg) in rats and 0.05 mg/kg/day (cumulative dose/cycle: 0.15 mg/kg) in dogs. PNU-159548 showed minimal cardiotoxicity, when compared with doxorubicin in the chronic rat model at a dose level inducing similar myelotoxicity. Animal pharmacokinetics, carried out in mice, rats, and dogs, was characterized by high volumes of distribution, plasma clearance of the same order of the hepatic blood flow, and short terminal half-life. These findings support the conclusion that PNU-159548 is an excellent candidate for clinical trials in the treatment of cancer.
4-去甲氧基-3'-脱氨基-3'-氮丙啶基-4'-甲基磺酰基柔红霉素（PNU-159548）属于一类新型抗肿瘤化合物（称为烷基环素），目前正在进行II期临床试验。在本研究中，我们调查了该化合物的体外和体内抗肿瘤活性、药代动力学和毒理学特征。PNU-159548在体外培养的小鼠和人类癌细胞中显示出良好的细胞毒性活性，50%生长抑制的平均浓度为15.8 ng/ml。该药物经静脉注射和口服给药后，在体内对快速增殖的小鼠白血病和生长缓慢的可移植人类异种移植物显示出强大的抗肿瘤功效。在无毒剂量下，PNU-159548可使卵巢癌、乳腺癌和人类小细胞肺癌完全消退并治愈。在研究的16种模型中，包括结肠癌、胰腺癌、胃癌和肾癌、星形细胞瘤和黑色素瘤，有14种被发现对PNU-159548敏感。此外，PNU-159548对颅内植入肿瘤也有效。毒理学研究表明，骨髓抑制是小鼠和狗的主要毒性。单次给药后的最大耐受剂量，小鼠为2.5 mg/kg体重，大鼠为1.6 mg/kg，狗为0.3 mg/kg。在循环研究中，大鼠的最大耐受剂量为0.18 mg/kg/天（累积剂量/周期：0.54 mg/kg），狗为0.05 mg/kg/天（累积剂量/周期：0.15 mg/kg）。与多柔比星在慢性大鼠模型中诱导相似骨髓毒性的剂量水平相比，PNU-159548显示出最小的心脏毒性。在小鼠、大鼠和狗身上进行的动物药代动力学特征为分布容积大、血浆清除率与肝血流量相当、终末半衰期短。这些发现支持了PNU-159548是癌症治疗临床试验的优秀候选药物这一结论。
