[Leukemogenesis and new therapy development: the example of chronic myelogenous leukemia].
During the past ten years, the improvements of our understanding of cellular signal transduction pathways provide new targets for drug therapies. Chronic myeloid leukemia (CML), a malignant hematopoietic stem cell disorder, is characterised by an acquired genetic abnormality: the Philadelphia chromosome (Ph) and its molecular counterpart, the oncogene BCR-ABL. The latter, which is translated in an active BCR-ABL protein, exhibited a deregulated tyrosine kinase activity inducing malignant transformation. Produced from the 2-phenylaminopyrimidine class, a novel synthetic inhibitor, identified as CGP57148 (STI571), inhibits tyrosine kinase activity of c-ABL, BCR-ABL, PDGF-R and c-kit at micromolar concentrations. It suppresses the proliferation of the majority of BCR-ABL positive cell lines. The phases I-II clinical trials in CML have demonstrated promising results, especially in the chronic phase of the disease. STI571 is an original therapeutic approach which may be used as a model for the development of other drugs in cancer.
Etienne
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Laboratoire de greffe de moelle, Université Victor-Ségalen UMR CNRS 5540, 146, rue Léo-Saignat, 33076 Bordeaux, France.
Mahon
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D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000502:physiology; D001549:Benzamides; D016026:Bone Marrow Transplantation; D019496:Cancer Vaccines / Q000627:therapeutic use; D002448:Cell Adhesion / Q000502:physiology; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005544:Forecasting; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D000068877:Imatinib Mesylate; D016898:Interferon-alpha / Q000627:therapeutic use; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000628:therapy*; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology*; D010677:Philadelphia Chromosome; D010879:Piperazines / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000627:therapeutic use; D015398:Signal Transduction / Q000502:physiology
D000970:Antineoplastic Agents; D001549:Benzamides; D019496:Cancer Vaccines; D004791:Enzyme Inhibitors; D016898:Interferon-alpha; D016376:Oligonucleotides, Antisense; D015514:Oncogene Proteins, Fusion; D010879:Piperazines; D011743:Pyrimidines; C406060:abl-bcr fusion protein, human; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl