This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Loadman, P. M. Articles by Duncan, R. Search for Related Content PubMed PubMed Citation Articles by Loadman, P. M. Articles by Duncan, R.

Pharmacokinetics of PK1 and Doxorubicin in Experimental Colon Tumor Models with Differing Responses to PK1¹

Clinical Oncology Unit, University of Bradford, Bradford BD7 1DP [P. M. L., M. C. B., J. A. D., W. M. A-S.], and School of Pharmacy, University of London, London WC1N 1A [R. D.], United Kingdom

PK1 is a synthetic N-(2-hydroxypropyl)methacrylamide copolymer-doxorubicin (dox) conjugate currently undergoing Phase II evaluation in the United Kingdom. We have studied the activity of PK1 in three murine colon tumor models that differ in terms of morphology and vascularization in an attempt to determine which factors are most important in the tumor response to PK1. Vascular permeability was evaluated with Evans Blue, and pharmacokinetic studies in MAC15A and MAC26 used high-performance liquid chromatography to monitor 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 MAC15A tumors, which possess enhanced perfusion and retention, but not against MAC26 tumors, although MAC15A was also responsive to PKI when grown as avascular micrometastatic deposits in the lung. Pharmacokinetic studies showed similar levels of PK1 in both tumors. Peak tumor levels of released dox were 7-fold greater in the responsive MAC15A tumor (53 µg·ml^-1) compared with the less responsive MAC26 tumor (7.7 µg·ml^-1) and more than 18-fold greater in MAC15A than when free dox was given. These differences in response correlated also with an increased lysosomal activity of cathepsin B. Calculated AUCs for intratumoral dox released were 431 µg·h·g^-1 and 775 µg·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 shown that activity and the pharmacokinetics of PK1 and released dox are dependent on both the vascular properties and enzyme content of the tumors. These studies are likely to have clinical implications as aggressive tumors are known to have increased protease activity.

This article has been cited by other articles:

				B. Chen, B. W. Pogue, X. Zhou, J. A. O'Hara, N. Solban, E. Demidenko, P. J. Hoopes, and T. Hasan Effect of Tumor Host Microenvironment on Photodynamic Therapy in a Rat Prostate Tumor Model Clin. Cancer Res., January 15, 2005; 11(2): 720 - 727. [Abstract] [Full Text] [PDF]

				S. Bien, C. A. Ritter, M. Gratz, B. Sperker, J. Sonnemann, J. F. Beck, and H. K. Kroemer Nuclear Factor-{kappa}B Mediates Up-Regulation of Cathepsin B by Doxorubicin in Tumor Cells Mol. Pharmacol., May 1, 2004; 65(5): 1092 - 1102. [Abstract] [Full Text] [PDF]

				A. M. Mansour, J. Drevs, N. Esser, F. M. Hamada, O. A. Badary, C. Unger, I. Fichtner, and F. Kratz A New Approach for the Treatment of Malignant Melanoma: Enhanced Antitumor Efficacy of an Albumin-binding Doxorubicin Prodrug That Is Cleaved by Matrix Metalloproteinase 2 Cancer Res., July 15, 2003; 63(14): 4062 - 4066. [Abstract] [Full Text] [PDF]