Management of chronic myeloid leukemia: targets for molecular therapy.
Chronic myeloid leukemia (CML) is a hematopoietic disorder characterized by malignant expansion of bone marrow stem cells. Currently, the only unequivocally curative treatment for CML is allogeneic stem cell transplant. Unfortunately, a large proportion of CML patients are ineligible for such treatment and alternative forms of therapy must be employed. Conventional chemotherapy makes use of compounds, such as hydroxyurea, that are cytotoxic for actively dividing cells. Although effective, these agents are not selective for the leukemic clone and this is the cause of undesirable side effects. Moreover, as the disease progresses patients frequently become refractory to chemotherapy. In recent years, knowledge of the molecular pathology of CML has allowed the development of drugs that selectively target the malignant cells: imatinib mesylate is the most prominent example. These agents are selective because they target molecular determinants that are exclusively deregulated in the leukemic cells. In this review we consider some of the novel developments in this field. Particular emphasis is given to chemical agents that target the Bcr-Abl oncoprotein. The latter affords an excellent opportunity for therapy since CML, in contrast to many other human malignancies, is likely caused by the activity of a single oncoprotein. Furthermore, it is believed that Bcr-Abl continues to play a central role throughout the course of the disease.
Barnes
David J
DJ
Department of Haematology, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, London, UK.
Melo
Junia V
JV
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D019468:Disease Management; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology / Q000627:therapeutic use; D016337:RNA, Catalytic / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D016376:Oligonucleotides, Antisense; D016337:RNA, Catalytic; D016044:Fusion Proteins, bcr-abl