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

Journal Article


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.

Publication Date


  • 1998

Citation


  • Hang, M. T. N., Ranson, M., Saunders, D. N., Liang, X. M., Bunn, C. L., & Baker, M. S. (1998). Pharmacokinetics and biodistribution of recombinant human plasminogen activator inhibitor type 2 (PAI-2) in control and tumour xenograft-bearing mice. Fibrinolysis and Proteolysis, 12(3), 145-154. doi:10.1016/S0268-9499(98)80296-8

Scopus Eid


  • 2-s2.0-0031759137

Start Page


  • 145

End Page


  • 154

Volume


  • 12

Issue


  • 3

Place Of Publication


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.

Publication Date


  • 1998

Citation


  • Hang, M. T. N., Ranson, M., Saunders, D. N., Liang, X. M., Bunn, C. L., & Baker, M. S. (1998). Pharmacokinetics and biodistribution of recombinant human plasminogen activator inhibitor type 2 (PAI-2) in control and tumour xenograft-bearing mice. Fibrinolysis and Proteolysis, 12(3), 145-154. doi:10.1016/S0268-9499(98)80296-8

Scopus Eid


  • 2-s2.0-0031759137

Start Page


  • 145

End Page


  • 154

Volume


  • 12

Issue


  • 3

Place Of Publication