PRECLINICAL TOXICOLOGY OF A NOVEL POLYMERIC ANTITUMOR AGENT - HPMA COPOLYMER-DOXORUBICIN (PK1)

N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin (PK1) i s a novel polymeric anticancer agent containing doxorubicin (approxima tely 8 wt%) bound to the polymer backbone via a Gly-Phe-Leu-Gly peptid yl 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 ta ken on days 3, 7 and 14 for haematological examination and clinical ch emistry. At day 14 all animals were sacrificed for necropsy. In a mult iple 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 1 2.0 or 22.5 mg/kg (mice) or 3 and 5 mg/kg(rats), After 31 days 10 anim als from each group were sacrificed far necropsy and the remainder wer e sacrificed after 59 days, Blood samples were taken 3 days after admi nistration of each dose and at the end of the experiment, and mine sam ples were collected on the day prior to sacrifice. Mortality in the si ngle dose mouse and multiple dose rat studies was low, In the multiple dose mouse study 4/10 animals were killed in extremis before the sche duled day 31 and all animals died before day 37. PK1 induced a reducti on in WBC and platelets in rats and mice shortly after treatment and R BC at later times, and in the single dose study alanine and aspartate aminotransferase levels were elevated at higher doses. Liver damage wa s seen only in rat tissue during histological examination. Other histo logical changes induced by PK1 include thymic and testicular atrophy, bone marrow depletion gastrointestinal tract changes and in the multip le dose study an increase in nuclear size in the proximal tubules of t he kidney (although no changes in urine were seen). Recovery fi om the se effects was seen in rats at 59 days. A PK1 dose of 20 mg/m(2) (doxo rubicin equivalent) was recommended as a safe dose for the start of Ph ase I clinical trials.