| Sign In to gain access to subscriptions and/or personal tools. |
DOI: 10.1177/096032719801700204 Preclinical toxicology of a novel polymeric antitumour agent: HPMA copolymerdoxorubicin (PK1)Centre for Polymer Therapeutics, The School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, UK, CRC Phase I/II Clinical Trials Committee
BIBRA International Woodmansterne Road, Carshalton, Surrey SM5 4DS, UK, CRC Phase I/II Clinical Trials Committee
Cancer Research Campaign, 10 Cambridge Terrace, London NW1 4Jl, UK, CRC Phase I/II Clinical Trials Committee 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 collectedonthe day prior to sacrifice.Mortality inthe 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.
Key Words: HPMA copolymer doxorubicin • PK1 • toxicity • drug targeting
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||
 |
|
|
 |
|
Sign In to gain access to subscriptions and/or personal tools.
