Pharmacokinetics and biodistribution of recombinant human plasminogen activator inhibitor type 2 (PAI-2) in control and tumour xenograft-bearing mice

M. T N Hang, M. Ranson*, D. N. Saunders, X. M. Liang, C. L. Bunn, M. S. Baker

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

Abstract

Objective: Previous studies have shown that the endogenous overexpression 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 determined in a xenograft Nu/Nu mouse model of human colon cancer and compared to control mice (i.e. without a human xenograft tumour). Design: 125I-labelled recombinant PAI-2 was injected intravenously and the pharmacokinetics and biodistribution determined in control Nu/Nu mice or mice carrying a subcutaneous HCT116 hum an colon cancer xenograft. Results: The clearance of 125I-PAI-2 from mouse plasma was found to be a biphasic process and radioactivity was excreted via the urine in a degraded form. While radioactivity corresponding to intact PAI-2 localized to tumour xenograft tissues quickly (after 1 min, peaking after 30-60 min at 1.3% of injected dose), the majority of radioactivity localized to major organs (e.g. liver, kidneys) 5 min after intravenous injection of 125I-PAI-2 in both turnout bearing and control mice. However, radioactivity was cleared more rapidly from these organs when compared to tumour tissues. Moreover, multiple injections of 125I-PAI-2 resulted in an increased uptake of radioactivity in tumour xenografts without accompanying increases in the liver. Furthermore, the clearance rate was markedly increased by the presence of a tumour xenograft indicating the requirement to undertake pharmacokinetic studies in diseased as well as control animals. Conclusion: Our results provide important information concerning the pharmacokinetics and biodistribution of PAI-2 and indicates that the presence of a tumour may affect these parameters. Moreover, the localization and accumulation of PAI- 2 in tumour tissues argues for a potential therapeutic use in human cancer.

Original languageEnglish
Pages (from-to)145-154
Number of pages10
JournalFibrinolysis and Proteolysis
Volume12
Issue number3
Publication statusPublished - 1998
Externally publishedYes

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