TY - JOUR
T1 - Preclinical evaluation of 213Bi-labeled plasminogen activator inhibitor type 2 in an orthotopic murine xenogenic model of human breast carcinoma
AU - Stutchbury, Tamantha K
AU - Al-Ejeh, Fares
AU - Stillfried, Gillian E
AU - Croucher, David R
AU - Andrews, John
AU - Irving, David
AU - Links, Matthew
AU - Ranson, Marie
PY - 2007/1
Y1 - 2007/1
N2 - 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 (α-PAI-2) in multiple carcinoma models. Here, we present preclinical toxicologic and efficacy assessment of α-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 α-PAI-2 should interact with any uPA-expressing host cells. In this model, single bolus doses up to 36 mCi/kg α-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 × 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 × 5 was the most efficacious schedule. In conclusion, we have determined a safe dose and schedule of α-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. Copyright © 2007 American Association for Cancer Research.
AB - 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 (α-PAI-2) in multiple carcinoma models. Here, we present preclinical toxicologic and efficacy assessment of α-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 α-PAI-2 should interact with any uPA-expressing host cells. In this model, single bolus doses up to 36 mCi/kg α-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 × 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 × 5 was the most efficacious schedule. In conclusion, we have determined a safe dose and schedule of α-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. Copyright © 2007 American Association for Cancer Research.
UR - http://www.scopus.com/inward/record.url?eid=2-s2.0-33846804080&partnerID=MN8TOARS
U2 - 10.1158/1535-7163.MCT-06-0264
DO - 10.1158/1535-7163.MCT-06-0264
M3 - Article
SN - 1535-7163
VL - 6
SP - 203
EP - 212
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 1
ER -