Preliminary data suggestive of a novel translational approach to mesothelioma treatment: imatinib mesylate with gemcitabine or pemetrexed.
BACKGROUND
Malignant mesothelioma is a cancer which is refractory to current treatments. Imatinib mesylate is a selective inhibitor of tyrosine kinases such as bcr-abl, c-Kit, c-Fms and platelet derived growth factor receptor beta (PDGFRbeta). PDGFRbeta is often overexpressed in mesothelioma cells and is a therapeutic target for imatinib in some solid tumours. A study was undertaken to assess whether imatinib alone or combined with chemotherapeutic agents may be effective for treating mesothelioma.


METHODS
Cultures from mesothelioma MMP, REN and ISTMES2 cell lines were treated with imatinib alone or in combination with a chemotherapeutic agent.


RESULTS
Imatinib induced cytotoxicity and apoptosis selectively on PDGFRbeta positive mesothelioma cells via blockade of receptor phosphorylation and interference with the Akt pathway. Of the chemotherapeutic agents tested in combination with imatinib, a synergistic effect was obtained with gemcitabine and pemetrexed.


CONCLUSIONS
This study provides a rationale for a novel translational approach to the treatment of mesothelioma which relies on enhancement of tumour chemosensitivity by inhibition of Akt.
Bertino
Pietro
P
DISCAFF Department and DFBC Center, University of Piemonte Orientale A Avogadro, 28100 Novara, Italy.
Porta
Camillo
C
Barbone
Dario
D
Germano
Serena
S
Busacca
Sara
S
Pinato
Sabrina
S
Tassi
Giancarlo
G
Favoni
Roberto
R
Gaudino
Giovanni
G
Mutti
Luciano
L
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001549:Benzamides; D016923:Cell Death; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D016236:Genes, fms; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D000068877:Imatinib Mesylate; D008654:Mesothelioma / Q000188:drug therapy* / Q000378:metabolism; D000068437:Pemetrexed; D010879:Piperazines / Q000008:administration & dosage; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
D001549:Benzamides; D005971:Glutamates; D010879:Piperazines; D011743:Pyrimidines; D000068437:Pemetrexed; D003841:Deoxycytidine; D006147:Guanine; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D020797:Receptor, Platelet-Derived Growth Factor beta; D051057:Proto-Oncogene Proteins c-akt; D000093542:Gemcitabine