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Research Articles: Therapeutics, Targets, and Development

Preclinical evaluation of ²¹³Bi-labeled plasminogen activator inhibitor type 2 in an orthotopic murine xenogenic model of human breast carcinoma

¹ School of Biological Sciences, University of Wollongong, Wollongong, New South Wales, Australia; ² JLA Bioprocess Consulting, Berowra, New South Wales, Australia; ³ Diabetes Vaccine Development Centre, c/- School of Population Health, University of Melbourne, Melbourne, Victoria, Australia; and ⁴ Cancer Care Centre and University of New South Wales Clinical School, St. George Hospital, Sydney, New South Wales, Australia

Requests for reprints: Marie Ranson, School of Biological Sciences, University of Wollongong, Wollongong, NSW 2522, Australia. Phone: 61-2-42213291; Fax: 61-2-42214135. E-mail: mranson{at}uow.edu.au

Abstract

Tumor-associated urokinase plasminogen activator (uPA) is a critical marker of invasion and metastasis, has strong prognostic relevance, and is thus a potential therapeutic target. Experimental data published to date has established the proof-of-principle of uPA targeting by ²¹³Bi-labeled plasminogen activator inhibitor type 2 (-PAI-2) in multiple carcinoma models. Here, we present preclinical toxicologic and efficacy assessment of -PAI-2 in mice, using both single and multiple-dose schedules, administered by an i.p. route. We also present novel data showing that human PAI-2 inhibited murine uPA and was specifically endocytosed by murine fibroblast cells. This diminishes potential problems associated with species specificity of the targeting reagent in toxicologic assessments as human -PAI-2 should interact with any uPA-expressing host cells. In this model, single bolus doses up to 36 mCi/kg -PAI-2 did not reach the maximum tolerated dose (MTD). The MTD for a multiple fractionated (once daily for 5 days) administration schedule was determined to lie between 4.8 and 6.0 mCi/kg/d x 5. Comparison of the tumor growth rates and survival using sub-MTD single and multiple-dose schedules in an orthotopic human breast carcinoma xenograft murine model indicated that 4.8 mCi/kg/d x 5 was the most efficacious schedule. In conclusion, we have determined a safe dose and schedule of -PAI-2 administration in mice, thus confirming that it is an efficacious therapeutic modality against tumor growth. This will allow detailed safety evaluation in a second species and for the initiation of human studies. [Mol Cancer Ther 2007;6(1):203–11]

Grant support: National Health and Medical Research Council Development grant 213119 and an Australian Postgraduate Award (F. Al-ejeh, G.E. Stillfried, and D.R. Croucher).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Current address for F. Al-ejeh: Experimental Therapeutics Laboratory, Hanson Institute, Frome Road, Adelaide, SA 5000, Australia.

Received 5/ 9/06; revised 10/11/06; accepted 11/16/06.