Preclinical toxicology of a novel polymeric antitumour agent: HPMA copolymer-doxorubicin (PK1)
Preclinical toxicology of a novel polymeric antitumour agent: HPMA copolymer-doxorubicin (PK1)
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DOI：
10.1191/096032798678908378
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发表时间：
1998-02-01
影响因子：
2.8
通讯作者：
Burtles, S
中科院分区：
文献类型：
--
作者：
Duncan, R;Coatsworth, JK;Burtles, S
N-（2-羟丙基）甲基丙烯酰胺（HPMA）共聚物-阿霉素（PK 1）是一种新型的聚合物抗癌剂，其含有通过Gly-Phe-Leu-Gly肽基连接物结合到聚合物主链上的阿霉素（约8wt%）。MF 1小鼠单次静脉注射后PK 1的近似LD 50为63 mg/kg（多柔比星当量）。以22.5或45 mg/kg对MF 1小鼠单次给予PK 1，并在第3、7和14天采集血样用于血液学检查和临床化学。在第14天，处死所有动物进行尸检。在多次给药研究中，将PK 1静脉内给予MF 1小鼠或Wistar大鼠（每组20只动物）每周一次，连续5周，剂量为12.0或22.5 mg/kg（小鼠）或3和5 mg/kg（大鼠），31天后，每组10只动物被处死进行尸检，其余动物在59天后被处死，在每次给药后3天和实验结束时采集血样，并在处死前一天采集血样。单次给药小鼠和多次给药大鼠研究中的死亡率较低，在多次给药小鼠研究中，4/10只动物在计划的第31天前濒死处死，所有动物在第37天前死亡。PK 1在给药后不久诱导大鼠和小鼠的WBC和血小板减少，随后诱导RBC减少，在单次给药研究中，较高剂量的丙氨酸和天冬氨酸转氨酶水平升高。在组织学检查期间仅在大鼠组织中观察到肝损伤。PK 1诱导的其他组织学变化包括胸腺和睾丸萎缩、骨髓耗竭胃肠道变化以及多次给药研究中肾脏近端小管的核大小增加（尽管未观察到尿液变化）。在第59天，在大鼠中观察到这些效应的恢复。建议将20 mg/m2（阿霉素当量）的PK 1剂量作为I期临床试验开始时的安全剂量。
N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin (PK1) is a novel polymeric anticancer agent containing doxorubicin (approximately 8 wt%) bound to the polymer backbone via a Gly-Phe-Leu-Gly peptidyl linker. The approximate LD50 of PK1 in MF1 mice after a single i.v. injection was 63 mg/kg (doxorubicin-equivalent). Single doses of PK1 were administered to MF1 mice at 22.5 or 45 mg/kg and blood samples taken on days 3, 7 and 14 for haematological examination and clinical chemistry. At day 14 all animals were sacrificed for necropsy. In a multiple dose study, PK1 was administered i.v. to MF1 mice or Wistar rats (20 animals per group) weekly for five consecutive weeks at doses of 12.0 or 22.5 mg/kg (mice) or 3 and 5 mg/kg(rats), After 31 days 10 animals from each group were sacrificed far necropsy and the remainder were sacrificed after 59 days, Blood samples were taken 3 days after administration of each dose and at the end of the experiment, and mine samples were collected on the day prior to sacrifice. Mortality in the single dose mouse and multiple dose rat studies was low, In the multiple dose mouse study 4/10 animals were killed in extremis before the scheduled day 31 and all animals died before day 37. PK1 induced a reduction in WBC and platelets in rats and mice shortly after treatment and RBC at later times, and in the single dose study alanine and aspartate aminotransferase levels were elevated at higher doses. Liver damage was seen only in rat tissue during histological examination. Other histological changes induced by PK1 include thymic and testicular atrophy, bone marrow depletion gastrointestinal tract changes and in the multiple dose study an increase in nuclear size in the proximal tubules of the kidney (although no changes in urine were seen). Recovery fi om these effects was seen in rats at 59 days. A PK1 dose of 20 mg/m(2) (doxorubicin equivalent) was recommended as a safe dose for the start of Phase I clinical trials.