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Title: Therapeutic efficacy of 177Lu-CHX-A''-DTPA-hu3S193 radioimmunotherapy in prostate cancer is enhanced by EGFR inhibition or docetaxel chemotherapy.
Austin Authors: Kelly, Marcus P;Lee, Sze Ting ;Lee, Fook-Thean;Smyth, Fiona E;Davis, Ian D;Brechbiel, Martin W;Scott, Andrew M 
Affiliation: Tumour Targeting Laboratory, Ludwig Institute for Cancer Research, Melbourne Centre for ClinicalSciences, Austin Hospital, Heidelberg, Victoria, Australia
Issue Date: 1-Jan-2009
Publication information: The Prostate; 69(1): 92-104
Abstract: This study investigated the biodistribution and therapeutic efficacy of Lutetium-177 (177Lu) radiolabeled anti-Lewis Y monoclonal antibody hu3S193 radioimmunotherapy (RIT) in mice bearing prostate cancer xenografts. The ability of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor AG1478 and docetaxel chemotherapy to enhance the efficacy of RIT was also assessed in vivo.The in vitro cytotoxicity of 177Lu labeled hu3S193 on Le(y) positive DU145 prostate cancer cells was assessed using proliferation assays, with induction of apoptosis measured by ELISA. The in vivo biodistribution and tumor localization of 177Lu-hu3S193 was assessed in mice bearing established DU145 tumor xenografts. The efficacy and maximum tolerated dose of 177Lu-hu3S193 RIT in vivo was determined by a dose escalation study. EGFR inhibitor AG1478 or docetaxel chemotherapy was administered at sub-therapeutic doses in conjunction with RIT in vivo.177Lu-hu3S193 mediated significant induction of cytotoxicity and apoptosis in vitro. In vivo analysis of 177Lu-hu3S193 biodistribution demonstrated specific targeting of DU145 prostate cancer xenografts, with maximal tumor uptake of 33.2 +/- 3.9%ID/g observed at 120 hr post-injection. In RIT studies, 177Lu-hu3S193 caused specific and dose-dependent inhibition of prostate cancer tumor growth. A maximum tolerated dose of 350 microCi was determined for 177Lu-hu3S193. Combination of 177Lu-hu3S193 RIT with EGFR inhibitor AG1478 or docetaxel chemotherapy both significantly improved efficacy.177Lu-hu3S193 RIT is effective as a single agent in the treatment of Le(y) positive prostate cancer models. The enhancement of RIT by AG1478 or docetaxel indicates the promise of combined modality strategies.
Gov't Doc #: 18942092
DOI: 10.1002/pros.20856
Type: Journal Article
Subjects: Animals
Antibodies, Monoclonal.therapeutic use
Antibodies, Monoclonal, Humanized
Antineoplastic Agents.therapeutic use
Apoptosis.radiation effects
Cell Division.drug effects
Cell Line, Tumor
Combined Modality Therapy
Dose-Response Relationship, Radiation
Enzyme Inhibitors.pharmacology
Lutetium.therapeutic use
Mice, Inbred BALB C
Mice, Nude
Pentetic Acid.analogs & derivatives
Phosphorylation.drug effects
Prostatic Neoplasms.drug therapy.radiotherapy
Radiation-Sensitizing Agents.therapeutic use
Radioisotopes.therapeutic use
Receptor, Epidermal Growth Factor.antagonists & inhibitors.metabolism
Taxoids.therapeutic use
Xenograft Model Antitumor Assays
Appears in Collections:Journal articles

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