Rational approaches to the design of therapeutics targeting molecular markers: the case of chronic myelogenous leukemia.
Progress in understanding the molecular basis of signal transmission and transduction has contributed substantially to clarifying the mechanisms of leukemogenesis and of leukemia progression and has led to the identification of a number of specific molecular targets for treatment. Chronic myeloid leukemia (CML) has provided one of the best models, as the identification of a leukemia-specific hybrid tyrosine kinase (BCR-ABL, p210, p190) has led to the identification and the successful therapeutic application of a powerful tyrosine kinase inhibitor, imatinib. The BCR-ABL fusion gene is the result of a reciprocal translocation between the long arms of chromosomes 9 and 22, t(9;22)(q34;q11), which characterizes more than 95% of the cases of CML. The resulting chimeric proteins (P210 and P190), which retain a constitutively activated tyrosine kinase activity, have a causative role in the genesis of the leukemia process. In agreement with this observation, BCR-ABL tyrosine kinase inhibitors have recently emerged as powerful new therapeutic tools, obtaining extraordinary results in early chronic-phase CML as well as in more advanced phases of the disease. Although these results represent a remarkable breakthrough, there are still numerous issues, such as the emergence of resistance, that remain unsolved and that will need further investigation. In spite of its low incidence, CML remains a paradigmatic model for understanding the pathogenesis and therapeutic options of human leukemias.
Saglio
Giuseppe
G
Dept. of Clinical and Biological Sciences of the University of Turin, San Luigi Hospital, Gonzole 10, 10043, Orbassano-Torino, Italy. giuseppe.saglio@unito.it
Morotti
Alessandro
A
Mattioli
Giovanna
G
Messa
Emanuela
E
Giugliano
Emilia
E
Volpe
Gisella
G
Rege-Cambrin
Giovanna
G
Cilloni
Daniela
D
D001549:Benzamides; D014408:Biomarkers, Tumor; D002892:Chromosomes, Human, Pair 22 / Q000648:ultrastructure; D002899:Chromosomes, Human, Pair 9 / Q000648:ultrastructure; D003593:Cytoplasm / Q000378:metabolism; D018450:Disease Progression; D015195:Drug Design; D004345:Drug Industry / Q000639:trends; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D013997:Time Factors
D001549:Benzamides; D014408:Biomarkers, Tumor; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl