title: Preclinical activity of melflufen (J1) in ovarian cancer.
abstract: Ovarian cancer carries a significant mortality. Since symptoms tend to be minimal, the disease is often diagnosed when peritoneal metastases are already present. The standard of care in advanced ovarian cancer consists of platinum-based chemotherapy combined with cytoreductive surgery. Unfortunately, even after optimal cytoreduction and adjuvant chemotherapy, most patients with stage III disease will develop a recurrence. Intraperitoneal administration of chemotherapy is an alternative treatment for patients with localized disease. The pharmacological and physiochemical properties of melflufen, a peptidase potentiated alkylator, raised the hypothesis that this drug could be useful in ovarian cancer and particularily against peritoneal carcinomatosis. In this study the preclinical effects of melflufen were investigated in different ovarian cancer models. Melflufen was active against ovarian cancer cell lines, primary cultures of patient-derived ovarian cancer cells, and inhibited the growth of subcutaneous A2780 ovarian cancer xenografts alone and when combined with gemcitabine or liposomal doxorubicin when administered intravenously. In addition, an intra- and subperitoneal xenograft model showed activity of intraperitoneal administered melflufen for peritoneal carcinomatosis, with minimal side effects and modest systemic exposure. In conclusion, results from this study support further investigations of melflufen for the treatment of peritoneal carcinomatosis from ovarian cancer, both for intravenous and intraperitoneal administration.
authors.affiliation: Department of Surgery, Laboratory of Experimental Surgery, Ghent University, Ghent, Belgium.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Carlier
authors.affiliation: Department of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala University, Uppsala, Sweden.
authors.forename: Sara
authors.initials: S
authors.lastname: Strese
authors.affiliation: Department of Oncology and Pathology, Karolinska Biomics Center, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Kristina
authors.initials: K
authors.lastname: Viktorsson
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Ebba
authors.initials: E
authors.lastname: Velander
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Nygren
authors.affiliation: Oncopeptides AB, Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Uustalu
authors.affiliation: Department of Oncology and Pathology, Karolinska Biomics Center, Karolinska Institutet, Stockholm, Sweden.|Oncopeptides AB, Stockholm, Sweden.
authors.forename: Therese
authors.initials: T
authors.lastname: Juntti
authors.affiliation: Department of Oncology and Pathology, Karolinska Biomics Center, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Rolf
authors.initials: R
authors.lastname: Lewensohn
authors.affiliation: Department of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala University, Uppsala, Sweden.
authors.forename: Rolf
authors.initials: R
authors.lastname: Larsson
authors.affiliation: Present address: InSpira Medical AB, Tyresö, Sweden.
authors.forename: Jack
authors.initials: J
authors.lastname: Spira
authors.affiliation: Radiation Oncology and Experimental Cancer Research, Laboratory of Experimental Cancer Research, Ghent University, Ghent, Belgium.
authors.forename: Elly
authors.initials: E
authors.lastname: De Vlieghere
authors.affiliation: Department of Surgery, Laboratory of Experimental Surgery, Ghent University, Ghent, Belgium.
authors.forename: Wim P
authors.initials: WP
authors.lastname: Ceelen
authors.affiliation: Department of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala University, Uppsala, Sweden.|Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Joachim
authors.initials: J
authors.lastname: Gullbo
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D045744:Cell Line, Tumor; D065426:Cytoreduction Surgical Procedures; D018572:Disease-Free Survival; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced; D007274:Injections, Intraperitoneal; D008558:Melphalan / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051379:Mice; D016513:Mice, SCID; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: C585069:melflufen; D010649:Phenylalanine; D008558:Melphalan
keywords: in vivo; intraperitoneal treatment; melflufen; ovarian cancer; preclinical