In vitro and In vivo Antitumor Activity of a Novel Alkylating Agent Melphalan-flufenamide Against Multiple Myeloma Cells
Dharminder Chauhan,Arghya Ray,Kristina Viktorsson,Jack Spira,Claudia E. Paba-Prada,Nikhil C. Munshi,Paul G. Richardson,Rolf Lewensohn,Kenneth C. Anderson +8 more
Reads0
Chats0
TLDR
The preclinical study supports clinical evaluation of mel-flufen to enhance therapeutic potential of melphalan, overcome drug-resistance, and improve multiple myeloma patient outcome.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 IC 50 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. Clin Cancer Res; 19(11); 3019–31. ©2013 AACR .read more
Citations
More filters
Journal ArticleDOI
New Drugs and Novel Mechanisms of Action in Multiple Myeloma in 2013: A Report From the International Myeloma Working Group (IMWG)
Enrique M. Ocio,Paul G. Richardson,S V Rajkumar,Antonio Palumbo,M.V. Mateos,Robert Z. Orlowski,Shaji Kumar,Saad Z. Usmani,Saad Z. Usmani,D. Roodman,Ruben Niesvizky,H. Einsele,KC Anderson,Meletios A. Dimopoulos,Hervé Avet-Loiseau,Ulf-Henrik Mellqvist,Ingemar Turesson,Giampaolo Merlini,Rik Schots,Philip L. McCarthy,Leif Bergsagel,C. S. Chim,J.J. Lahuerta,Jatin P. Shah,A. Reiman,Joseph R. Mikhael,Sonja Zweegman,S. Lonial,Raymond L. Comenzo,Wee Joo Chng,Philippe Moreau,Pieter Sonneveld,Heinz Ludwig,B. Durie,J. S. Miguel +34 more
TL;DR: This work reviews the biological rationale for the use of the most important new agents for treating Multiple myeloma, and discusses data from already approved and active agents (including second- and third-generation proteasome inhibitors, immunomodulatory agents and alkylators).
Journal ArticleDOI
Therapeutic journery of nitrogen mustard as alkylating anticancer agents: Historic to future perspectives.
TL;DR: A comprehensive review of the medicinal chemistry aspects in the development of various classes of nitrogen mustards (mechlorethamine, chlorambucil, melphalan, cyclophosphamide and steroidal based nitrogenmustards) including the historical and the latest developments in these areas are discussed.
Journal ArticleDOI
A 13 mer LNA-i-miR-221 inhibitor restores drug-sensitivity in melphalan-refractory multiple myeloma cells
Annamaria Gullà,Maria Teresa Di Martino,Maria Eugenia Gallo Cantafio,Eugenio Morelli,Nicola Amodio,Cirino Botta,Maria Rita Pitari,Santo Giovanni Lio,Domenico Britti,Maria Angelica Stamato,Teru Hideshima,Nikhil C. Munshi,Nikhil C. Munshi,Kenneth C. Anderson,Pierosandro Tagliaferri,Pierfrancesco Tassone,Pierfrancesco Tassone +16 more
TL;DR: The findings provide the proof of concept that LNA-i-miR-221 can reverse melphalan resistance in preclinical models of multiple myeloma, providing the framework for clinical trials to overcome drug resistance, and improve patient outcome in multiple myELoma.
Journal ArticleDOI
Melflufen and Dexamethasone in Heavily Pretreated Relapsed and Refractory Multiple Myeloma
Paul G. Richardson,Albert Oriol,Alessandra Larocca,Joan Bladé,Michele Cavo,Paula Rodriguez-Otero,Xavier Leleu,Omar Nadeem,John W. Hiemenz,Hani Hassoun,Cyrille Touzeau,Adrian Alegre,Agne Paner,Christopher Maisel,Amitabha Mazumder,Anastasios Raptis,Jan S. Moreb,Kenneth C. Anderson,Jacob P. Laubach,Sara Thuresson,Marcus Thuresson,Catriona Byrne,Johan Harmenberg,Nicolaas A Bakker,Maria-Victoria Mateos,Horizon (Op ) Investigators +25 more
TL;DR: Melflufen plus dexamethasone showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated RRMM, including those with triple-class–refractory and extramedullary disease.
Journal ArticleDOI
Blockade of deubiquitylating enzyme Rpn11 triggers apoptosis in multiple myeloma cells and overcomes bortezomib resistance
Yan Song,Shijun Li,Arghya Ray,Deepika Sharma Das,Jun Qi,Mehmet Kemal Samur,YT Tai,Nikhil C. Munshi,Ruben D. Carrasco,D Chauhan,KC Anderson +10 more
TL;DR: The preclinical data provide the rationale for targeting DUB enzyme Rpn11 upstream of 20S proteasome to enhance cytotoxicity and overcome proteasomesome inhibitor resistance in MM.
References
More filters
Journal ArticleDOI
Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors
Ting-Chao Chou,Paul Talalay +1 more
TL;DR: A generalized method for analyzing the effects of multiple drugs and for determining summation, synergism and antagonism has been proposed and has been used to analyze experimental data obtained from enzymatic, cellular and animal systems.
Journal ArticleDOI
A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myélome.
Michel Attal,Jean-Luc Harousseau,Anne-Marie Stoppa,Jean-Jacques Sotto,Jean-Gabriel Fuzibet,Jean-François Rossi,Philippe Casassus,Hervé Maisonneuve,Thierry Facon,Norbert Ifrah,Catherine Payen,Régis Bataille +11 more
TL;DR: The response rate among the patients who received high-dose therapy was 81 percent, whereas it was 57 percent in the group treated with conventional chemotherapy (P<0.001).
Journal ArticleDOI
ATM Phosphorylates Histone H2AX in Response to DNA Double-strand Breaks
TL;DR: The results clearly establish ATM as the major kinase involved in the phosphorylation of H2AX and suggest that ATM is one of the earliest kinases to be activated in the cellular response to double-strand breaks.
Journal ArticleDOI
High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma.
J. Anthony Child,Gareth J. Morgan,Faith E. Davies,Roger G. Owen,Sue E. Bell,Kim Hawkins,Julia Brown,Mark T. Drayson,Peter Selby +8 more
TL;DR: High-dose therapy with autologous stem-cell rescue is an effective first-line treatment for patients with multiple myeloma who are younger than 65 years of age and trend toward a greater survival benefit in the group of patients with a poor prognosis.
Journal ArticleDOI
Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy.
Teru Hideshima,Dharminder Chauhan,Dharminder Chauhan,Yoshihito Shima,Yoshihito Shima,Noopur Raje,Noopur Raje,Faith E. Davies,Faith E. Davies,Yu-Tzu Tai,Yu-Tzu Tai,Steven P. Treon,Steven P. Treon,Boris Lin,Boris Lin,Robert L. Schlossman,Robert L. Schlossman,Paul G. Richardson,Paul G. Richardson,George W. Muller,George W. Muller,David I. Stirling,David I. Stirling,Kenneth C. Anderson,Kenneth C. Anderson +24 more
TL;DR: Clinical activity of Thal against MM that is refractory to conventional therapy is demonstrated and mechanisms of anti-tumor activity of thalidomide and its potent analogs (immunomodulatory drugs [IMiDs]) are delineated.
Related Papers (5)
Aminopeptidase N (CD13) as a target for cancer chemotherapy
Melflufen plus dexamethasone in relapsed and refractory multiple myeloma (O-12-M1): a multicentre, international, open-label, phase 1-2 study.
Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy.
Ujjawal H. Gandhi,Robert F. Cornell,Arjun Lakshman,Zhubin Gahvari,Elizabeth McGehee,Megan Jagosky,Ridhi Gupta,William Varnado,Mark A. Fiala,Saurabh Chhabra,Ehsan Malek,Joshua Mansour,Barry Paul,Alyssa Barnstead,Saranya Kodali,Amarendra K. Neppalli,Michaela Liedtke,Swapna Narayana,Kelly N. Godby,Yubin Kang,Ankit Kansagra,Elvira Umyarova,Emma C. Scott,Parameswaran Hari,Ravi Vij,Saad Z. Usmani,Natalie S. Callander,Shaji Kumar,Luciano J. Costa +28 more
Oral selinexor-dexamethasone for triple-class refractory multiple myeloma
Ajai Chari,Dan T Vogl,Maria Gavriatopoulou,Ajay K. Nooka,Andrew Yee,Carol Ann Huff,Philippe Moreau,David Dingli,Craig E. Cole,S. Lonial,Meletios A. Dimopoulos,A. Keith Stewart,Joshua Richter,Ravi Vij,Sascha Tuchman,Marc S Raab,Katja Weisel,Michel Delforge,Robert F Cornell,David Kaminetzky,James E. Hoffman,Luciano J. Costa,Terri L. Parker,Moshe Yair Levy,Martin Schreder,Nathalie Meuleman,Laurent Frenzel,Mohamad Mohty,Sylvain Choquet,Gary J. Schiller,Raymond L Comenzo,Monika Engelhardt,Thomas Illmer,Philip Vlummens,Chantal Doyen,Thierry Facon,Lionel Karlin,Aurore Perrot,Klaus Podar,Michael Kauffman,Sharon Shacham,Lingling Li,Shijie Tang,Carla Picklesimer,Jean-Richard Saint-Martin,Marsha Crochiere,Hua Chang,Samir Parekh,Yosef Landesman,Jatin Shah,Paul G. Richardson,Sundar Jagannath +51 more
Melflufen and Dexamethasone in Heavily Pretreated Relapsed and Refractory Multiple Myeloma
Paul G. Richardson,Albert Oriol,Alessandra Larocca,Joan Bladé,Michele Cavo,Paula Rodriguez-Otero,Xavier Leleu,Omar Nadeem,John W. Hiemenz,Hani Hassoun,Cyrille Touzeau,Adrian Alegre,Agne Paner,Christopher Maisel,Amitabha Mazumder,Anastasios Raptis,Jan S. Moreb,Kenneth C. Anderson,Jacob P. Laubach,Sara Thuresson,Marcus Thuresson,Catriona Byrne,Johan Harmenberg,Nicolaas A Bakker,Maria-Victoria Mateos,Horizon (Op ) Investigators +25 more