Della Torre P, Podestà A, Imondi A R, Moneta D, Sammartini U, Arrigoni C, Terron A, Brughera M
Worldwide Toxicology, Pharmacia and Upjohn, 20014 Nerviano, Milan, Italy.
Cancer Chemother Pharmacol. 2001 Apr;47(4):355-60. doi: 10.1007/s002800000240.
PNU-159548 (4-demethoxy-3'-deamino-3'aziridinyl-4'-methylsulphonyl-daunorubicin), a derivative of the anticancer idarubicin, has a broad spectrum of antitumoral activity in vitro and in vivo attributable to its DNA intercalating and alkylating properties. The present study was conducted to determine the cardiotoxic activity of PNU-159548 relative to doxorubicin in a chronic rat model sensitive to anthracycline-induced cardiomyopathy.
Young adult male rats were allocated to the following treatment groups: group 1, PNU-159548 vehicle control (colloidal dispersion); group 2, doxorubicin control (saline); groups 3, 4, 5, 6, and 7, PNU-159548 at 0.12, 0.25, 0.50, 0.75, and 1.0 mg/kg, respectively; and group 8, 1.0 mg/kg doxorubicin. Treatments were administered intravenously once weekly for 4 weeks (first sacrifice time) or for 7 weeks (rats killed at weeks 8, 12, 22, 27, or 35). Body weights, organ weights, serum chemistry, hematology, serum troponin-T, and cardiac histopathology were followed throughout the study.
Doxorubicin caused irreversible cardiomyopathy evident at week 4 in some rats and progressing in severity in all rats by week 8. There were also marked myelotoxicity, increased liver and kidney weights, testicular atrophy, and about 20% mortality by week 27 in doxorubicin-treated rats. The deaths were attributed to cardiomyopathy and/or nephropathy. PNU-159548 caused a dose-dependent myelotoxicity, with the dose of 0.5 mg/kg per week being equimyelotoxic to 1.0 mg/kg per week doxorubicin. PNU-159548 also caused an increase in liver weight that was reversible and a non-reversible testicular atrophy but, unlike doxorubicin, had no effect on kidney weight. At equimyelotoxic doses, the cardiotoxicity caused by PNU-159548, expressed as the mean total score, was less than one-twentieth of that induced by doxorubicin, and much less than that predicted on the basis of its content of idarubicin, which is in turn markedly less cardiotoxic than doxorubicin.
The novel cytotoxic antitumor derivative, PNU-159548, is significantly less cardiotoxic than doxorubicin at equimyelosuppressive doses. The combination of intercalating and alkylating activities within the same molecule without the cardiotoxic side effects of anthracyclines makes PNU-159548 an excellent candidate for clinical development in oncology.
PNU-159548（4-去甲氧基-3'-去氨基-3'-氮丙啶基-4'-甲基磺酰基柔红霉素）是抗癌药伊达比星的衍生物，因其具有DNA嵌入和烷基化特性，在体外和体内均具有广泛的抗肿瘤活性。本研究旨在确定在对蒽环类药物诱导的心肌病敏感的慢性大鼠模型中，PNU-159548相对于多柔比星的心脏毒性活性。
将年轻成年雄性大鼠分配到以下治疗组：第1组，PNU-159548溶媒对照（胶体分散液）；第2组，多柔比星对照（生理盐水）；第3、4、5、6和7组，PNU-159548剂量分别为0.12、0.25、0.50、0.75和1.0mg/kg；第8组，1.0mg/kg多柔比星。每周静脉给药一次，共4周（首次处死时间）或7周（在第8、12、22、27或35周处死大鼠）。在整个研究过程中监测体重、器官重量、血清化学、血液学、血清肌钙蛋白-T和心脏组织病理学。
多柔比星导致不可逆的心肌病，在第4周时一些大鼠中明显可见，并在第8周时所有大鼠中严重程度逐渐加重。多柔比星治疗的大鼠中还存在明显的骨髓毒性、肝脏和肾脏重量增加、睾丸萎缩，到第27周时死亡率约为20%。死亡归因于心肌病和/或肾病。PNU-159548引起剂量依赖性骨髓毒性，每周0.5mg/kg的剂量与每周1.0mg/kg多柔比星的骨髓毒性相当。PNU-159548还导致肝脏重量增加，这是可逆的，以及不可逆的睾丸萎缩，但与多柔比星不同，对肾脏重量没有影响。在等效骨髓毒性剂量下，PNU-159548引起的心脏毒性，以平均总分表示，不到多柔比星诱导毒性的二十分之一，且远低于根据其伊达比星含量预测的毒性，而伊达比星的心脏毒性又明显低于多柔比星。
新型细胞毒性抗肿瘤衍生物PNU-159548在等效骨髓抑制剂量下的心脏毒性明显低于多柔比星。同一分子内兼具嵌入和烷基化活性且无蒽环类药物的心脏毒性副作用，使得PNU-159548成为肿瘤学临床开发的优秀候选药物。
