Melflufen - a peptidase-potentiated alkylating agent in clinical trials.

@article{Wickstrm2017MelflufenA,
  title={Melflufen - a peptidase-potentiated alkylating agent in clinical trials.},
  author={Malin Wickstr{\"o}m and Peter Nygren and Rolf Larsson and Johan Harmenberg and Jakob Lindberg and Per Sj{\"o}berg and Markus Jerling and Fredrik Lehmann and Paul Richardson and Kenneth Anderson and Dharminder Chauhan and Joachim Gullbo},
  journal={Oncotarget},
  year={2017}
}
Aminopeptidases like aminopeptidase N (APN, also known as CD13) play an important role not only in normal cellular functioning but also in the development of cancer, including processes like tumor cell invasion, differentiation, proliferation, apoptosis, motility, and angiogenesis. An increased expression of APN has been described in several types of human malignancies, especially those characterized by fast-growing and aggressive phenotypes, suggesting APN as a potential therapeutic target… Expand
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The novel alkylating prodrug melflufen (J1) inhibits angiogenesis in vitro and in vivo.
TLDR
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. Expand
The alkylating prodrug J1 can be activated by aminopeptidase N, leading to a possible target directed release of melphalan.
TLDR
A role of APN in the activation of the melphalan prodrug J1 and subsequently, its cytotoxic effects is demonstrated and data suggest that J1 may be activated in a tumor selective manner. Expand
Activity of Hydrolytic Enzymes in Tumour Cells is a Determinant for Anti-tumour Efficacy of the Melphalan Containing Prodrug J1
TLDR
The results show that the activity of the dipeptide mustards is highly dependent on intracellular hydrolysis, which result in rapid intrACEllular release of the alkylating unit in cells with high enzymatic activity. Expand
In vitro and in vivo anti-leukemic activity of the peptidase-potentiated alkylator melflufen in acute myeloid leukemia
TLDR
Melflufen demonstrates high and significant preclinical activity in AML and further clinical evaluation seem warranted in this disease, as well as in a patient derived xenograft study. Expand
The novel melphalan prodrug J1 inhibits neuroblastoma growth in vitro and in vivo
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The melphalan prodrug J1 is highly active in models of neuroblastoma in vitro and in vivo, encouraging further clinical development in this patient group. Expand
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The ex vivo profile of J 1 suggests that further evaluation of J1 as the alkylating agent in for example aggressive breast cancer might be of particular interest, preferentially in combination with DNA-topoisomerase II inhibitors like etoposide. Expand
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The prevalence and possible function of APN in malignant diseases, mainly solid tumors, as well as its “drugability” evaluated in preclinical in vivo models are discussed, and a brief overview of current clinical trials focused on APN is provided. Expand
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An update on the biological and pharmacological profiles of known natural and synthetic APN inhibitors and current status on their potential use as therapeutic agents is discussed with regard to toxicity and specificity. Expand
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The results indicate that the activity of these compounds not only relies on their chemical reactivity, but also on active biological interactions such as transport across membranes and/or enzymatic liberation of reactive molecular entities. Expand
In vitro and in vivo activity of melflufen (J1)in lymphoma
TLDR
This study confirms previous reports of a targeting related potency superiority of melflufen compared to that of melphalan and appears to be a candidate for further evaluation in the treatment of this group of malignant diseases. Expand
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