title: In vitro and in vivo effects of a recombinant anti-PSMA immunotoxin in combination with docetaxel against prostate cancer.
abstract: Docetaxel (DOC) is used for the first-line treatment of castration resistant prostate cancer (CPRC). However, the therapeutic effects are limited, only about one half of patients respond to the therapy and severe side effects possibly lead to discontinuation of treatment. Therefore, actual research is focused on the development of new DOC-based combination treatments. In this study we investigated the antitumor effects of a recombinant immunotoxin targeting the prostate specific membrane antigen (PSMA) in combination with DOC in vitro and in vivo. The immunotoxin consists of an anti-PSMA single chain antibody fragment (scFv) as binding and a truncated form of Pseudomonas aeruginosa Exotoxin A (PE40) as toxin domain. The immunotoxin induced apoptosis and specifically reduced the viability of androgen-dependent LNCaP and androgen-independent C4-2 prostate cancer cells. A synergistic cytotoxic activity was observed in combination with DOC with IC50 values in the low picomolar or even femtomolar range. Moreover, combination treatment resulted in an enhanced antitumor activity in a C4-2 SCID mouse xenograft model. This highlights the immunotoxin as a promising therapeutic agent for a future DOC-based combination therapy of CPRC.
authors.affiliation: Department of Urology, Medical Center, University of Freiburg, Freiburg, Germany.
authors.forename: Marta
authors.initials: M
authors.lastname: Michalska
authors.affiliation: Department of Urology, Medical Center, University of Freiburg, Freiburg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Schultze-Seemann
authors.affiliation: Institute for Medical Biometry and Statistics, Medical Center, University of Freiburg, Freiburg, Germany.
authors.forename: Lioudmila
authors.initials: L
authors.lastname: Bogatyreva
authors.affiliation: Institute for Medical Biometry and Statistics, Medical Center, University of Freiburg, Freiburg, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Hauschke
authors.affiliation: Department of Urology, Medical Center, University of Freiburg, Freiburg, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Wetterauer
authors.affiliation: Department of Urology, Medical Center, University of Freiburg, Freiburg, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Wolf
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000077143:Docetaxel; D043425:Glutamate Carboxypeptidase II / Q000494:pharmacology*; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011471:Prostatic Neoplasms; D057127:Single-Chain Antibodies / Q000494:pharmacology; D043823:Taxoids / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000954:Antigens, Surface; D000922:Immunotoxins; D057127:Single-Chain Antibodies; D043823:Taxoids; D000077143:Docetaxel; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II
keywords: PSMA; chemotherapy; docetaxel; immunotoxin; prostate cancer