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

Journal Article


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. [Mol Cancer Ther 2007;6(1):203-11].

Authors


  •   Stutchbury, Tamantha
  •   Al-Ejeh, Fares (external author)
  •   Stillfried, Gillian Erika. (external author)
  •   Croucher, David R. (external author)
  •   Andrews, John (external author)
  •   Irving, David (external author)
  •   Links, Matthew (external author)
  •   Ranson, Marie

Publication Date


  • 2007

Citation


  • Stutchbury, T. K., Al-Ejeh, F., Stillfried, G. Erika., Croucher, D., Andrews, J., Irving, D., Links, M. & Ranson, M. (2007). Preclinical evaluation of 213Bi-labeled plasminogen activator inhibitor type 2 in an orthotopic murine xenogenic model of human breast carcinoma. Molecular Cancer Therapeutics, 6 (1), 203-212.

Scopus Eid


  • 2-s2.0-33846804080

Ro Metadata Url


  • http://ro.uow.edu.au/hbspapers/1905

Has Global Citation Frequency


Number Of Pages


  • 9

Start Page


  • 203

End Page


  • 212

Volume


  • 6

Issue


  • 1

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. [Mol Cancer Ther 2007;6(1):203-11].

Authors


  •   Stutchbury, Tamantha
  •   Al-Ejeh, Fares (external author)
  •   Stillfried, Gillian Erika. (external author)
  •   Croucher, David R. (external author)
  •   Andrews, John (external author)
  •   Irving, David (external author)
  •   Links, Matthew (external author)
  •   Ranson, Marie

Publication Date


  • 2007

Citation


  • Stutchbury, T. K., Al-Ejeh, F., Stillfried, G. Erika., Croucher, D., Andrews, J., Irving, D., Links, M. & Ranson, M. (2007). Preclinical evaluation of 213Bi-labeled plasminogen activator inhibitor type 2 in an orthotopic murine xenogenic model of human breast carcinoma. Molecular Cancer Therapeutics, 6 (1), 203-212.

Scopus Eid


  • 2-s2.0-33846804080

Ro Metadata Url


  • http://ro.uow.edu.au/hbspapers/1905

Has Global Citation Frequency


Number Of Pages


  • 9

Start Page


  • 203

End Page


  • 212

Volume


  • 6

Issue


  • 1