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

Hang, Min; Ranson, Marie; Saunders, Darren N.; Liang, Xiao; Bunn, C. L.; Baker, Mark S.

doi:10.1016/s0268-9499(98)80296-8

Cited by 16 publications

(19 citation statements)

References 27 publications

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“…The pharmacokinetics and biodistribution of human recombinant 125 I-labelled PAI2 in both control mice and mice bearing human colon cancer (uPA-positive HCT116 cell line) xenografts have been established (Hang et al, 1998). Such studies indicate that invasive and metastatic tumour cells, shown consistently to contain active uPA, would be accessible to and targeted by exogenously administered PAI2.…”

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confidence: 99%

Preclinical studies of targeted α therapy for breast cancer using 213Bi-labelled-plasminogen activator inhibitor type 2

et al. 2003

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The control of micrometastatic breast cancer remains problematic. To this end, we are developing a new adjuvant therapy based on 213 Bi-PAI2, in which an a-emitting nuclide ( 213 Bi) is chelated to the plasminogen activator inhibitor-2 (PAI2). PAI2 targets the cellsurface receptor bound urokinase plasminogen activator (uPA), which is involved with the metastatic spread of cancer cells. We have successfully labelled and tested recombinant human PAI2 with the a radioisotope 213 Bi to produce 213 Bi-PAI2, which is highly cytotoxic towards breast cancer cell lines. In this study, the 2-day postinoculation model, using MDA-MB-231 breast cancer cells, was shown to be representative of micrometastatic disease. Our in vivo efficacy experiments show that a single local injection of 213 Bi-PAI2 can completely inhibit the growth of tumour at 2 days postcell inoculation, and a single systemic (i.p.) administration at 2 days causes tumour growth inhibition in a dose-dependent manner. The specific role of uPA as the target for 213 Bi-PAI2 therapy was determined by PAI2 pretreatment blocking studies. In vivo toxicity studies in nude mice indicate that up to 100 mCi of 213 Bi-PAI2 is well tolerated. Thus, 213 Bi-PAI2 is successful in targeting isolated breast cancer cells and preangiogenic cell clusters. These results indicate the promising potential of 213 Bi-PAI2 as a novel therapeutic agent for micrometastatic breast cancer.

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confidence: 99%

Preclinical studies of targeted α therapy for breast cancer using 213Bi-labelled-plasminogen activator inhibitor type 2

et al. 2003

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“…route. Similar patterns of [ 125 I]PAI-2 biodistribution in nude mice were observed by i.p., i.v., or s.c. administration (19), indicating that the former is a suitable surrogate route for systemic administration of a-PAI-2 in these small animal models. The radioactivity of each injection preparation was measured using an Atomlab 100 Dose Calibrator (Protronic Technologies, Victoria, Melbourne, Australia) immediately before and following i.p.…”

Section: Radiolabeling Of Pai-2-diethylenetriaminetriacetic Acid Withmentioning

confidence: 97%

“…a-PAI-2 was shown to specifically kill uPA-expressing tumor cells in vitro in a dose-dependent manner (16,17) and to be efficacious in preliminary studies using mouse models of human tumors (17,18). Radio-iodinated PAI-2 has also been shown to localize in human colorectal uPA-expressing tumor xenografts in nude mouse models (19), thus providing proofof-principle data for the uPA-targeting capability of PAI-2. Given that the efficient and rapid inhibition of carcinoma cell surface uPAR bound uPA by PAI-2 results in specific receptor-mediated endocytosis of the uPAR/uPA/PAI-2 complex (8,20), PAI-2 is thus efficiently and specifically able to deliver and concentrate attached cytotoxins within targeted cells.…”

Section: Introductionmentioning

confidence: 92%

“…At this stage, the animals were euthanized (overdose of inhaled CO 2 ) and the internal organs were macroscopically examined for signs of toxicity. Because previous studies found no toxicity associated with the targeting agent PAI-2 (7,17,18) and biodistribution of the radiolabeled compound to major organs was limited to the kidneys and liver (19), histologic assessments were restricted to these organs and one lymphoid organ, the spleen. Blood smears were taken and blood was also collected into K3 EDTA and Z serum gel minicollect tubes (Greiner Bio-one) for hematology and serum blood biochemistry to complete the toxicologic assessment.…”

Section: Toxicity Studies For Determination Of Maximum Tolerated Dosementioning

confidence: 99%

“…We have previously undertaken detailed pharmacokinetic and biodistribution analyses of PAI-2 in mice with and without tumors (19). The focus of this study was to determine a safe and efficacious dose schedule of a-PAI-2 against orthotopic human breast carcinoma xenograft growth in mice.…”

Section: Introductionmentioning

confidence: 99%

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

Stutchbury

Al-Ejeh

Stillfried

et al. 2007

Molecular Cancer Therapeutics

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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 (A-PAI-2) in multiple carcinoma models. Here, we present preclinical toxicologic and efficacy assessment of A-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 A-PAI-2 should interact with any uPA-expressing host cells. In this model, single bolus doses up to 36 mCi/kg A-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 Â 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 Â 5 was the most efficacious schedule. In conclusion, we have determined a safe dose and schedule of A-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.

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Urokinase-type plasminogen activator and its receptor in colorectal cancer: Independent prognostic factors of metastasis and cancer-specific survival and potential therapeutic targets

et al. 2000

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

Cited by 16 publications

References 27 publications

Preclinical studies of targeted α therapy for breast cancer using 213Bi-labelled-plasminogen activator inhibitor type 2

Preclinical studies of targeted α therapy for breast cancer using 213Bi-labelled-plasminogen activator inhibitor type 2

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

Urokinase-type plasminogen activator and its receptor in colorectal cancer: Independent prognostic factors of metastasis and cancer-specific survival and potential therapeutic targets

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