PHARMACOKINETICS AND BIODISTRIBUTION OF RECOMBINANT HUMAN PLASMINOGEN-ACTIVATOR INHIBITOR TYPE-2 (PAI-2) IN CONTROL AND TUMOR XENOGRAFT-BEARING MICE

Objective: Previous studies have shown that the endogenous overexpress ion of human plasminogen activator inhibitor type-2 (PAI-2) in tumour cells decrease their ability to grow and metastasise. The therapeutic utility of PAI-2, however, remains poorly evaluated. In this study the kinetics and biodistribution of recombinant human PAI-2 were determin ed in a xenograft Nu/Nu mouse model of human colon cancer and compared to control mice (i.e. without a human xenograft tumour). Design: I-12 5-labelled recombinant PAI-2 was injected intravenously and the pharma cokinetics and biodistribution determined in control Nu/Nu mice or mic e carrying a subcutaneous HCT116 human colon cancer xenograft. Results : The clearance of I-125-PAI-2 from mouse plasma was found to be a bip hasic process and radioactivity was excreted via the urine in a degrad ed form. While radioactivity corresponding to intact PAI-2 localized t o tumour xenograft tissues quickly (after 1 min, peaking after 30-60 m in at 1.3% of injected dose), the majority of radioactivity localized to major organs (e.g, liver, kidneys) 5 min after intravenous injectio n of I-125-PAI-2 in both tumour bearing and control mice. However, rad ioactivity was cleared more rapidly from these organs when compared to tumour tissues. Moreover, multiple injections of I-125-PAI-2 resulted in an increased uptake of radioactivity in tumour xenografts without accompanying increases in the liver. Furthermore, the clearance rate w as markedly increased by the presence of a tumour xenograft indicating the requirement to undertake pharmacokinetic studies in diseased as w ell as control animals. Conclusion: Our results provide important info rmation concerning the pharmacokinetics and biodistribution of PAI-2 a nd indicates that the presence of a tumour may affect these parameters . Moreover, the localization and accumulation of PAI-2 in tumour tissu es argues for a potential therapeutic use in human cancer.