title: Intravenous injection of an immunoconjugate (anti-PSA-IgG conjugated to 5-fluoro-2'-deoxyuridine) selectively inhibits cell proliferation and induces cell death in human prostate cancer cell tumors grown in nude mice.
abstract: Current chemotherapeutic and/or endocrine treatments for adenocarcinoma of the prostate are not delivered selectively to prostate cancer cells, therefore, they are used in very high doses that induce many unpleasant side effects in patients. New approaches are, therefore, needed to deliver drugs directly to prostate cancer cells to improve treatment effects. We hypothesized that antibody immunoglobulin G (IgG) against human prostate specific antigen (PSA) (anti-PSA-IgG) could function as a carrier protein for conjugated chemotherapeutic drugs (such as 5-fluoro-2'-deoxyuridine, doxorubicin, etc.) and that the immunoconjugate could be delivered selectively to PSA-producing neoplastic prostate. Immunoconjugate would then preferentially inhibit cell proliferation and induce cell death in PSA-producing tumor cells, but not in non-PSA-producing prostate cancer cells or other solid organs of the host. The short-term treatment effect could be assessed by measuring cell death and cell proliferation in tumor-bearing animals. We tested our hypothesis by intravenously injecting an immunoconjugate (anti-PSA-IgG-5-fu-2'-d) into nude mice with subcutaneous PSA-producing LNCaP or non-PSA-producing Du-145 prostate tumors. During 5 days of treatment, we observed that immunoconjugate was retained preferentially in PSA-producing LNCaP tumors where it produced cytotoxic effects in neoplastic prostate cells as revealed by decreased cell proliferation and increased cell death, but similar effects were not observed in non-PSA-producing Du-145 tumor cells or mouse organs. Analysis of untreated control mouse with LNCaP tumor, anti-PSA-IgG alone, anti-irrelevant-IgG-drug complex, and drug alone treatments indicated that there was little or no cytotoxic effects of these treatments on LNCaP and Du-145 tumors, and host organs. Our analysis of control and experimental data showed that the immunoconjugate was highly specific in imparting cytotoxic effects on LNCaP prostate tumors, but not on Du-145 tumors and mouse organs. Thus, we have shown that the immunoconjugate selectively delivered a chemotherapeutic drug to PSA-producing prostate tumor cells where it produced measurable cytotoxic effects on cell proliferation and cell death. This is the first report to show a successful delivery of a chemotherapeutic drug in the immunoconjugate to PSA-producing LNCaP prostate tumors in nude mice and without inducing cytotoxic effects on mouse organs.
authors.affiliation: Department of Genetics, University of Minnesota, St. Paul, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Sinha
authors.forename: B J
authors.initials: BJ
authors.lastname: Quast
authors.forename: P K
authors.initials: PK
authors.lastname: Reddy
authors.forename: M K
authors.initials: MK
authors.lastname: Elson
authors.forename: M J
authors.initials: MJ
authors.lastname: Wilson
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D005467:Floxuridine / Q000627:therapeutic use*; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007074:Immunoglobulin G / Q000627:therapeutic use*; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008819:Mice, Nude; D017430:Prostate-Specific Antigen / Q000276:immunology*; D011471:Prostatic Neoplasms / Q000473:pathology / Q000628:therapy*
chemical_list: D018796:Immunoconjugates; D007074:Immunoglobulin G; D005467:Floxuridine; D017430:Prostate-Specific Antigen