Pre-clinical studies on pharmacokinetics and pharmacodynamics of col-3, a matrix metalloproteinase inhibitor: Single agent and in combination with doxorubicin

Abstract

<P>THIS WAS AN EXPLORATORY PRECLINICAL STUDY ON THE POTENTIAL COMBINATION CHEMOTHERAPY OF COL-3, A MATRIX METALLOPROTEINASE INHIBITOR, WITH DOXORUBICIN (DOX), A CYTOTOXIC AGENT. COL-3 PHARMACOKINETICS AND COL-3/DOX PHARMACOKINETIC INTERACTION WERE EXAMINED IN RATS. ALSO, IN VIVO AND IN VITRO ANTITUMOR ACTIVITIES OF COL-3, GIVEN ALONE OR WITH DOX, WERE ASSESSED. COL-3 PHARMACOKINETICS WAS CHARACTERIZED BY A DISSOLUTION-RATE LIMITED ABSORPTION AND A SIGNIFICANT INTESTINAL EXCRETION, WHICH MAY ACCOUNT, IN PART, FOR THE LARGE PHARMACOKINETIC VARIABILITY OBSERVED IN PATIENTS. DOX-INDUCED GI TOXICITY CAUSED SIGNIFICANT REDUCTION IN COL-3 ORAL ABSORPTION, WARNING PHARMACOKINETIC INTERACTIONS BETWEEN COL-3 AND OTHER CYTOTOXIC AGENTS MAY BE POSSIBLE. COL-3 DID NOT SHOW APPARENT ANTITUMOR ACTIVITY, NOR POTENTIATE DOX ANTITUMOR EFFECT, IN MCF-7 BREAST CANCER ORTHOTOPIC MODEL. COL-3/DOX COMBINATION PRODUCED AN ANTAGONISTIC AND ADDITIVE EFFECT ON MCF-7 AND MDA-MB-231 CELLS, RESPECTIVELY. TO