Preclinical activity of melflufen (J1) in ovarian cancer
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Charlotte Carlier1,*, Sara Strese2,*, Kristina Viktorsson3, Ebba Velander4, Peter Nygren4, Maria Uustalu5, Therese Juntti3,5, Rolf Lewensohn3, Rolf Larsson2, Jack Spira6, Elly De Vlieghere7, Wim P. Ceelen1,#, Joachim Gullbo2,4,#
1Department of Surgery, Laboratory of Experimental Surgery, Ghent University, Ghent, Belgium
2Department of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala University, Uppsala, Sweden
3Department of Oncology and Pathology, Karolinska Biomics Center, Karolinska Institutet, Stockholm, Sweden
4Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
5Oncopeptides AB, Stockholm, Sweden
6Present address: InSpira Medical AB, Tyresö, Sweden
7Radiation Oncology and Experimental Cancer Research, Laboratory of Experimental Cancer Research, Ghent University, Ghent, Belgium
*These authors contributed equally to this work
#Shared senior authorship
Charlotte Carlier, email: Charlotte.email@example.com
Sara Strese, email: firstname.lastname@example.org
Keywords: ovarian cancer, melflufen, preclinical, in vivo, intraperitoneal treatment
Received: April 01, 2016 Accepted: July 19, 2016 Published: August 09, 2016
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.
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