Pharmacokinetics of PK1 and doxorubicin in experimental colon tumor modelswith differing responses to PK1

PK1 is a synthetic N-(2-hydroxypropyl) methacrylamide copolymer-doxorubicin (dox) conjugate currently undergoing Phase II evaluation in the United Kin gdom. We have studied the activity of PK1 in three murine colon tumor model s that differ in terms of morphology and vascularization in an attempt to d etermine which factors are most important in the tumor response to PK1, Vas cular permeability was evaluated with Evans flue, and pharmacokinetic studi es in MAC15A and MAC26 used high-performance liquid chromatography to monit or both PK1 uptake and dox release in the tumors. Cathepsin B activity was assessed using a specific substrate. PK1 (40 mg.kg(-1) dox equivalent) was significantly more effective than dox alone (10 mg kg(-1)) was against MAC1 5A tumors, which possess enhanced perfusion and retention, but not against MAC26 tumors, although MAC15A was also responsive to PKI when grown as avas cular micrometastatic deposits in the lung. Pharmacokinetic studies showed similar levels of PKI in both tumors. Peak tumor levels of released dox wer e 7-fold greater in the responsive MAC15A tumor (53 mu g.ml(-1)) compared w ith the less responsive MAC26 tumor (7.7 mu g.ml(-1)) and more than 18-fold greater in MAC15A than when free dox was given. These differences in respo nse correlated also with an increased lysosomal activity of cathepsin B, Ca lculated AUCs for intratumoral dox released were 431 mu g.h.g(-1) and 775 m u g.h.g(-1) for MAC15A and MAC26, respectively, These AUCs are 4-fold and 7 -fold higher, respectively, than when dox is given alone. This study has sh own that activity and the pharmacokinetics of PK1 and released dox are depe ndent on both the vascular properties and enzyme content of the tumors. The se studies are likely to have clinical implications as aggressive tumors ar e known to have increased protease activity.