title: Preclinical evaluation of 213Bi-labeled plasminogen activator inhibitor type 2 in an orthotopic murine xenogenic model of human breast carcinoma.
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 (213)Bi-labeled plasminogen activator inhibitor type 2 (alpha-PAI-2) in multiple carcinoma models. Here, we present preclinical toxicologic and efficacy assessment of alpha-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 alpha-PAI-2 should interact with any uPA-expressing host cells. In this model, single bolus doses up to 36 mCi/kg alpha-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 alpha-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.
authors.affiliation: School of Biological Sciences, University of Wollongong, Wollongong, NSW 2522, Australia.
authors.forename: Tamantha K
authors.initials: TK
authors.lastname: Stutchbury
authors.forename: Fares
authors.initials: F
authors.lastname: Al-Ejeh
authors.forename: Gillian E
authors.initials: GE
authors.lastname: Stillfried
authors.forename: David R
authors.initials: DR
authors.lastname: Croucher
authors.forename: John
authors.initials: J
authors.lastname: Andrews
authors.forename: David
authors.initials: D
authors.lastname: Irving
authors.forename: Matthew
authors.initials: M
authors.lastname: Links
authors.forename: Marie
authors.initials: M
authors.lastname: Ranson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology* / Q000633:toxicity; D001729:Bismuth / Q000032:analysis / Q000737:chemistry*; D001772:Blood Cell Count; D001943:Breast Neoplasms / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D020714:Maximum Tolerated Dose; D051379:Mice; D017396:Plasminogen Activator Inhibitor 2 / Q000008:administration & dosage* / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011868:Radioisotopes; D015203:Reproducibility of Results; D013379:Substrate Specificity / Q000187:drug effects; D016896:Treatment Outcome; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D017396:Plasminogen Activator Inhibitor 2; D011868:Radioisotopes; D014568:Urokinase-Type Plasminogen Activator; D001729:Bismuth