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Anticancer Activity of Melflufen: Preclinical Studies of a Novel Peptidase-Potentiated Alkylator
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Melflufen (melphalan flufenamide, chemical name L-melphalanyl-p-L-fluorophenylalanine ethyl ester hydrochloride, previously called J1) is a derivative of the classical alkylating agent melphalan. Melflufen is potentiated by hydrolytic cleavage by aminopeptidase N (APN), leading to high intracellular concentrations of alkylating moieties and subsequent cell death. Increased APN expression is associated with the malignant phenotype of several human cancers, including acute myeloid leukemia, lymphoma and ovarian cancer, and plays a functional role in tumor angiogenesis. Therefore investigations of melflufen activity in these malignancies as well as detailed studies of inhibition of angiogenesis are interesting. The aim of this project was to investigate the cytotoxic and antiangiogenic effect, in vitro and in vivo, of melflufen, compared to melphalan and other cytotoxic drugs used in the clinic.

We showed that melflufen was more effective than its parental drug melphalan in lymphoma, AML and ovarian cancer in cell lines as well as in primary patient samples. An improved in vitro therapeutic index was demonstrated by an increased cytotoxic activity in the patient samples compared to normal peripheral blood mononuclear cells (PBMCs). Furthermore, melflufen in combination with cytarabine was synergistic in an AML cell line in a sequence-dependent manor. Melflufen was shown effective in several animal models using lymphoma, AML and ovarian cell xenografts (single drug or in combination), including an intraperitoneal ovarian xenograft. Finally, we demonstrated that melflufen had antiangiogenic properties in several different models.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. , 55 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1145
Keyword [en]
cancertherapy, preclinical studies, melflufen, aminopeptidase-potentiated, cancer, angiogenesis
National Category
Clinical Medicine Cancer and Oncology
Research subject
Clinical Pharmacology
Identifiers
URN: urn:nbn:se:uu:diva-263133ISBN: 978-91-554-9371-4 (print)OAI: oai:DiVA.org:uu-263133DiVA: diva2:860872
Public defence
2015-12-12, Enghoffsalen, Akademiska sjukhuset, Ing 50, Uppsala, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2015-11-19 Created: 2015-09-27 Last updated: 2016-12-12
List of papers
1. In vitro and in vivo activity of melflufen (J1) in lymphoma
Open this publication in new window or tab >>In vitro and in vivo activity of melflufen (J1) in lymphoma
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(English)Article in journal (Other academic) Submitted
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-263131 (URN)
Available from: 2015-10-14 Created: 2015-09-27 Last updated: 2016-04-21
2. The peptidase-potentiated alkylator melflufen demonstrate antileukemic activity in acute myeloid leukemia, in vitro and in vivo
Open this publication in new window or tab >>The peptidase-potentiated alkylator melflufen demonstrate antileukemic activity in acute myeloid leukemia, in vitro and in vivo
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(English)Manuscript (preprint) (Other academic)
National Category
Clinical Medicine Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-263130 (URN)
Available from: 2015-10-14 Created: 2015-09-27 Last updated: 2016-01-13
3. Preclinical activity of melflufen (J1) in ovarian cancer
Open this publication in new window or tab >>Preclinical activity of melflufen (J1) in ovarian cancer
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2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 37, 59322-59335 p.Article in journal (Refereed) Published
Abstract [en]

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.

Keyword
ovarian cancer, melflufen, preclinical, in vivo, intraperitoneal treatment
National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-310031 (URN)10.18632/oncotarget.11163 (DOI)000387153900046 ()27528037 (PubMedID)
Available from: 2016-12-12 Created: 2016-12-09 Last updated: 2017-11-29Bibliographically approved
4. The novel alkylating prodrug melflufen (J1) inhibits angiogenesis in vitro and in vivo
Open this publication in new window or tab >>The novel alkylating prodrug melflufen (J1) inhibits angiogenesis in vitro and in vivo
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2013 (English)In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 86, no 7, 888-895 p.Article in journal (Refereed) Published
Abstract [en]

Aminopeptidase N (APN) has been reported to have a functional role in tumor angiogenesis and repeatedly reported to be over-expressed in human tumors. The melphalan-derived prodrug melphalan-flufenamide (melflufen, previously designated J1) can be activated by APN. This suggests that this alkylating prodrug may exert anti-angiogenic properties, which will possibly contribute to the anti-tumoral activity in vivo. This work presents a series of experiments designed to investigate this effect of melflufen. In a cytotoxicity assay we show that bovine endothelial cells were more than 200 times more sensitive to melflufen than to melphalan, in HUVEC cells the difference was more than 30-fold and accompanied by aminopetidase-mediated accumulation of intracellular melphalan. In the chicken embryo chorioallantoic membrane (CAM) assay it is indicated that both melflufen and melphalan inhibit vessel ingrowth. Two commercially available assays with human endothelial cells co-cultured with fibroblasts (TCS Cellworks AngioKit, and Essen GFP-AngioKit) also illustrate the superior anti-angiogenic effect of melflufen compared to melphalan. Finally, in a commercially available in vivo assay in mice (Cultrex DIVAA angio-reactor assay) melflufen displayed an anti-angiogenic effect, comparable to bevacizumab. In conclusion, this study demonstrates through all methods used, that melphalan-flufenamide besides being an alkylating agent also reveals anti-angiogenic effects in different preclinical models in vitro and in vivo. 

Keyword
Aminopeptidase N, Angiogenesis, Cancer, Prodrug, Antiangiogenic
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-209845 (URN)10.1016/j.bcp.2013.07.026 (DOI)000324976900005 ()
Available from: 2013-10-28 Created: 2013-10-28 Last updated: 2017-12-06Bibliographically approved

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