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Clin Cancer Res. 2013 Jun 1;19(11):3019-31. doi: 10.1158/1078-0432.CCR-12-3752. Epub 2013 Apr 12.

In vitro and in vivo antitumor activity of a novel alkylating agent, melphalan-flufenamide, against multiple myeloma cells.

Author information

1
The LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA. Dharminder_Chauhan@dfci.harvard.edu

Abstract

PURPOSE:

The alkylating agent melphalan prolongs survival in patients with multiple myeloma; however, it is associated with toxicities and development of drug-resistance. Here, we evaluated the efficacy of melphalan-flufenamide (mel-flufen), a novel dipeptide prodrug of melphalan in multiple myeloma.

EXPERIMENTAL DESIGN:

Multiple myeloma cell lines, primary patient cells, and the human multiple myeloma xenograft animal model were used to study the antitumor activity of mel-flufen.

RESULTS:

Low doses of mel-flufen trigger more rapid and higher intracellular concentrations of melphalan in multiple myeloma cells than are achievable by free melphalan. Cytotoxicity analysis showed significantly lower IC50 of mel-flufen than melphalan in multiple myeloma cells. Importantly, mel-flufen induces apoptosis even in melphalan- and bortezomib-resistant multiple myeloma cells. Mechanistic studies show that siRNA knockdown of aminopeptidase N, a key enzyme mediating intracellular conversion of mel-flufen to melphalan, attenuates anti-multiple myeloma activity of mel-flufen. Furthermore, mel-flufen-induced apoptosis was associated with: (i) activation of caspases and PARP cleavage; (ii) reactive oxygen species generation; (iii) mitochondrial dysfunction and release of cytochrome c; and (iv) induction of DNA damage. Moreover, mel-flufen inhibits multiple myeloma cell migration and tumor-associated angiogenesis. Human multiple myeloma xenograft studies showed a more potent inhibition of tumor growth in mice treated with mel-flufen than mice receiving equimolar doses of melphalan. Finally, combining mel-flufen with lenalidomide, bortezomib, or dexamethasone triggers synergistic anti-multiple myeloma activity.

CONCLUSION:

Our preclinical study supports clinical evaluation of mel-flufen to enhance therapeutic potential of melphalan, overcome drug-resistance, and improve multiple myeloma patient outcome.

PMID:
23584492
PMCID:
PMC4098702
DOI:
10.1158/1078-0432.CCR-12-3752
[Indexed for MEDLINE]
Free PMC Article
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