Duncan R, Coatsworth J K, Burtles S
Centre for Polymer Therapeutics, School of Pharmacy, University of London, UK.
Hum Exp Toxicol. 1998 Feb;17(2):93-104. doi: 10.1177/096032719801700204.
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 for 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 urine 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 from these effects was seen in rats at 59 days. A PK1 dose of 20 mg/m2 (doxorubicin equivalent) was recommended as a safe dose for the start of Phase I clinical trials.
N-(2-羟丙基)甲基丙烯酰胺（HPMA）共聚物-阿霉素（PK1）是一种新型聚合物抗癌剂，其中阿霉素（约8 wt%）通过甘氨酰-苯丙氨酰-亮氨酰-甘氨酸肽基连接子与聚合物主链相连。单次静脉注射后，PK1在MF1小鼠中的半数致死量（LD50）约为63 mg/kg（阿霉素等效剂量）。以22.5或45 mg/kg的剂量给MF1小鼠单次注射PK1，并在第3、7和14天采集血样进行血液学检查和临床化学检测。在第14天，处死所有动物进行尸检。在多剂量研究中，以12.0或22.5 mg/kg（小鼠）或3和5 mg/kg（大鼠）的剂量，每周给MF1小鼠或Wistar大鼠（每组20只动物）静脉注射PK1，连续注射五周。31天后，每组处死10只动物进行尸检，其余动物在59天后处死。每次给药后3天以及实验结束时采集血样，并在处死前一天收集尿样。单剂量小鼠研究和多剂量大鼠研究中的死亡率较低。在多剂量小鼠研究中，4/10只动物在预定的第31天之前濒死，所有动物在第37天之前死亡。PK1在治疗后不久会导致大鼠和小鼠白细胞和血小板减少，后期红细胞减少，在单剂量研究中，较高剂量时丙氨酸和天冬氨酸转氨酶水平升高。组织学检查仅在大鼠组织中发现肝脏损伤。PK1引起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，在多剂量研究中，肾脏近端小管细胞核大小增加（尽管尿液未见变化）。在59天时，大鼠的这些影响有所恢复。推荐20 mg/m2（阿霉素等效剂量）的PK1剂量作为I期临床试验开始时的安全剂量。
