title: Photochemical activation of MH3-B1/rGel: a HER2-targeted treatment approach for ovarian cancer.
abstract: HER2-targeted therapy has been shown to have limited efficacy in ovarian cancer despite frequent overexpression of this receptor. Photochemical internalization (PCI) is a modality for cytosolic drug delivery, currently undergoing clinical evaluation. In the present project we studied the application of PCI in combination with the HER2-targeted recombinant fusion toxin, MH3-B1/rGel, for the treatment of ovarian cancer. The SKOV-3 cell line, resistant to trastuzumab- and MH3-B1/rGel- monotherapy, was shown to respond strongly to PCI of MH3-B1/rGel to a similar extent as observed for the treatment-sensitive SK-BR-3 breast cancer cells. Extensive hydrolytic degradation of MH3-B1/rGel in acidic endocytic vesicles was indicated as the mechanism of MH3-B1/rGel resistance in SKOV-3 cells. This was shown by the positive Pearson's correlation coefficient between Alexa488-labeled MH3-B1/rGel and Lysotracker in SKOV-3 cells in contrast to the negative Pearson's correlation coefficient in SK-BR-3 cells. The application of PCI to induce the release of MH3-B1/rGel was also demonstrated to be effective on SKOV-3 xenografts. Application of PCI with MH3-B1/rGel was further found highly effective in the HER2 expressing HOC-7 and NuTu-19 ovarian cancer cell lines. The presented results warrant future development of PCI in combination with MH3-B1/rGel as a novel therapeutic approach in preclinical models of ovarian cancer.
authors.affiliation: Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
authors.forename: Bente
authors.initials: B
authors.lastname: Bull-Hansen
authors.affiliation: Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
authors.forename: Maria B
authors.initials: MB
authors.lastname: Berstad
authors.affiliation: Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
authors.forename: Kristian
authors.initials: K
authors.lastname: Berg
authors.affiliation: Immunopharmacology and Targeted Therapy Laboratory, Department of Experimental Therapeutics, MD Anderson Cancer Center, Houston, TX, USA.|Current address: The Scripps Research Institute, Department of Chemistry, La Jolla, CA, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Biochemistry, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
authors.forename: Ellen
authors.initials: E
authors.lastname: Skarpen
authors.affiliation: Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
authors.forename: Ane Sofie
authors.initials: AS
authors.lastname: Fremstedal
authors.affiliation: Immunopharmacology and Targeted Therapy Laboratory, Department of Experimental Therapeutics, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Rosenblum
authors.affiliation: Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
authors.forename: Qian
authors.initials: Q
authors.lastname: Peng
authors.affiliation: Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
authors.forename: Anette
authors.initials: A
authors.lastname: Weyergang
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology*; D051379:Mice; D058990:Molecular Targeted Therapy / Q000379:methods*; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D017319:Photosensitizing Agents / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D057127:Single-Chain Antibodies / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000922:Immunotoxins; D017319:Photosensitizing Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; D057127:Single-Chain Antibodies
keywords: HER2/neu/ErbB2; immunotoxin; ovarian cancer; photochemical internalization; photodynamic