Is AMN-107 a step forward from imatinib in the treatment of chronic myeloid leukaemia?
The Philadelphia (Ph) chromosome was the first consistent chromosome abnormality identified in cancer. It is found in 90% of patients with chronic myeloid leukaemia (CML) and in a subset of patients with acute lymphoblastic leukaemia. The effectiveness of the Bcr-Abl kinase inhibitor imatinib in these conditions reduces with advancing disease and/or the development of resistance to imatinib. AMN-107 inhibited the proliferation of haematopoietic cells expressing the mutants in Ph+ CML and acute lymphoblastic leukaemia with concentrations causing 50% inhibition of approximately 12 nM, making it more potent than imatinib. AMN-107 was also effective against several imatinib-resistant Bcr-Abl mutants, but not T3151. In mice transduced with Bcr-Abl, AMN-107 reduced mortality and tumour burden. In mice transduced with the E255V imatinib-resistant mutant of Bcr-Abl, AMN-107 delayed the onset of leukaemia. As AMN-107 is more potent and more selective for Bcr-Abl than imatinib, it may represent a step forward in the treatment of CML, but further animal (and then clinical) studies are needed to test this.
Doggrell
Sheila A
SA
Division of Health Practice, Auckland University of Technology-Akoranga Campus, Northcote, Auckland, New Zealand. s.doggrell@xtra.co.nz
D000818:Animals; D001549:Benzamides; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C498826:nilotinib