[Rich66]

: Expert Opin Drug Metab Toxicol. 2009 Aug 27. [Epub ahead of print]

ABCG2: the key to chemoresistance in cancer stem cells?

An Y, Ongkeko WM.
Stanford University School of Medicine, Stanford, CA 94305.
Multi-drug chemoresistance remains one of the most common reasons for chemotherapy failure. The membrane transporter protein ABCG2/BCRP1 has been shown in vitro to effectively reduce the intracellular concentrations of several prominent anticancer chemotherapeutic agents such as mitoxantrone and doxorubicin. Intriguingly, cancer stem cells are known to be characterized by multi-drug chemoresistance. Taking into account that the ABCG2(+) subset of tumor cells are often enriched with cells with cancer stem-like phenotypes, it has been proposed that ABCG2 activity underlies the ability of cancer cells to regenerate post-chemotherapy. Furthermore, we also review evidence suggesting that tyrosine kinase inhibitors, including imatinib and gefitinib, are both direct and downstream inactivators of ABCG2 and, therefore, serve as candidates to reverse cancer stem cell chemoresistance and potentially target cancer stem cells.

http://www.medicalnewstoday.com/articles/165763.php

10/1/09 Less toxic alternative to Imatinib

Masitinib - Targeted Therapy For Cancers, Inflammatory Diseases And Neurological Indications In new research published in the open-access, peer-reviewed scientific journal PLoS ONE, Dr Patrice Dubreuil and colleagues characterise the pharmacological profile of masitinib (AB1010), a novel tyrosine kinase inhibitor (TKI) that targets the stem cell factor (KIT), PDGFR and Lyn. Masitinib is the active pharmacological ingredient of the first ever registered veterinary anticancer drug, Masivet® (1). The main cellular targets of masitinib are mast cells, meaning this drug also has many potential non-oncology applications. Indeed, Masivet® is in phase II/III trials for canine atopic dermatitis, inflammatory bowel disease and arthritis; as well as feline asthma. Additionally, promising results have been reported from human clinical trials of masitinib in rheumatoid arthritis (2), asthma (3) and mastocytosis. Patrice Dubreuil from INSERM worked with scientists from several French research institutes and hospitals to carry out this work. He said, "This study shows that masitinib targets cell receptors known to be involved in various disease processes but due to its selectivity profile, it does not affect those associated with toxicity. In vitro, masitinib had greater activity and selectivity against KIT than the benchmark TKI, imatinib. Masitinib also more strongly inhibited mast cell degranulation, cytokine production, and migration than imatinib. In vivo, we show that masitinib can block tumour growth in mice". Alain Moussy from AB Science, a pharmaceutical company which is developing masitinib for multiple indications in human and animal medicine, commented, "This is an important paper for us, being the cornerstone publication of masitinib's inhibitory profile". Speaking about the drug's future development, he said, "Masitinib is in numerous phase II/III clinical trials for both human and veterinary medicine. We anticipate that masitinib will be effective for the treatment of KIT and PDGFR-dependent diseases, which include various cancers, inflammatory diseases, and neurological indications, and that it will have a better safety profile, especially regarding cardiotoxicity and carcinogenicity, than other KIT inhibitors." Citation: "Masitinib (AB1010), a Potent and Selective Tyrosine Kinase Inhibitor Targeting KIT." Dubreuil P, Letard S, Ciufolini M, Gros L, Humbert M, et al. (2009) PLoS ONE 4(9): e7258. doi:10.1371/journal.pone.0007258

Leuk Res. 2006 Oct;30(10):1249-52. Epub 2006 Mar 31.
Addition of sargramostim (GM-CSF) to imatinib results in major cytogenetic response in a patient with chronic myeloid leukemia.

Connor RF, Hurd D, Pettenati MJ, Koty P, Molnár I.
Department of Internal Medicine, Section on Hematology and Oncology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. rconnor@wfubmc.edu
Imatinib mesylate, an inhibitor of BCR/ABL tyrosine kinase, has remarkable activity in chronic myeloid leukemia resulting in an 87% major cytogenetic response. We describe a woman who failed to achieve any cytogenetic response after 2.5 years of imatinib, 400mg daily. When daily sargramostim (GM-CSF) 100 microg/m2 was added, cytogenetic studies revealed a gradual increase in percentage of normal cells from start, 4, 9, and 15 months at 0%, 10%, 55%, and 85%, respectively. She became transfusion independent after starting GM-CSF. The addition of GM-CSF to imatinib resulted in a clinical benefit and a major cytogenetic response in this patient.

PMID: 16580068 [PubMed - indexed for MEDLINE]