title: In vitro and preclinical targeted alpha therapy of human prostate cancer with Bi-213 labeled J591 antibody against the prostate specific membrane antigen.
abstract: Limited options for the treatment of prostate cancer have spurred the search for new therapies. One innovative approach is the use of targeted alpha therapy (TAT) to inhibit cancer growth, using an alpha particle emitting radioisotope such as (213)Bi. Because of its short range and high linear energy transfer (LET), alpha-particles may be particularly effective in the treatment of cancer, especially in inhibiting the development of metastatic tumors from micro-metastases. Prostate-specific membrane antigen (PSMA) is expressed in prostate cancer cells and the neovasculature of a wide variety of malignant neoplasms including lung, colon, breast and others, but not in normal vascular endothelium. The expression is further increased in higher-grade cancers, metastatic disease and hormone-refractory prostate cancer (PCA). J591 is one of several monoclonal antibodies (mabs) to the extracellular domain of PSMA. Chelation of J591 mab with (213)Bi forms the alpha-radioimmunoconjugate (AIC). The objective of this preclinical study was to design an injectable AIC to treat human prostate tumors growing subcutaneously in mice. The anti-proliferative effects of AIC against prostate cancer were tested in vitro using the MTS assay and in vivo with the nude mice model. Apoptosis was documented using terminal deoxynucleotidyl transferase [TdT]-mediated deoxyuridinetriphosphate [dUTP] nick end-labeling (TUNEL) assay, while proliferative index was assessed using the Ki-67 marker. We show that a very high density of PSMA is expressed in an androgen-dependent human PCA cell line (LNCaP-LN3) and in tumor xenografts from nude mice. We also demonstrate that the AIC extensively inhibits the growth of LN3 cells in vitro in a concentration-dependent fashion, causing the cells to undergo apoptosis. Our in vivo studies showed that a local AIC injection of 50 microCi at 2 days post-cell inoculation gave complete inhibition of tumor growth, whereas results for a non-specific AIC were similar to those for untreated mice. Further, after 1 and 3 weeks post-tumor appearance, a single (100 microCi/100 microl) intra-lesional injection of AIC can inhibit the growth of LN3 tumor xenografts (volume<100 mm(3)) in nude mice. Tumors treated with AIC decreased in volume from a mean 46+/-14 mm(3) in the first week or 71+/-15 mm(3) in the third week to non-palpable, while in control mice treated with a non-specific AIC using the same dose, tumor volume increased from 42 to 590 mm(3). There were no observed side effects of the treatment. Because of its in vitro cytotoxicity and these anti-proliferative properties in vivo, the (213)Bi-J591 conjugate has considerable potential as a new therapeutic agent for the treatment of prostate cancer.
authors.affiliation: Centre for Experimental Radiation Oncology, Cancer Care Centre, St George Hospital, Kogarah, NSW, Australia.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: Z
authors.initials: Z
authors.lastname: Tian
authors.forename: S M A
authors.initials: SM
authors.lastname: Rizvi
authors.forename: N H
authors.initials: NH
authors.lastname: Bander
authors.forename: B J
authors.initials: BJ
authors.lastname: Allen
mesh_terms: D000512:Alpha Particles; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000954:Antigens, Surface / Q000276:immunology*; D017209:Apoptosis; D001729:Bismuth / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D005434:Flow Cytometry; D043425:Glutamate Carboxypeptidase II / Q000276:immunology*; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use; D007124:Immunoenzyme Techniques; D020287:In Situ Nick-End Labeling; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D016499:Radioimmunotherapy; D011868:Radioisotopes / Q000627:therapeutic use*
chemical_list: D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D018796:Immunoconjugates; C478680:J591 monoclonal antibody; D019394:Ki-67 Antigen; D011868:Radioisotopes; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II; D001729:Bismuth