Tim R Randolph1. 1. Department of Clinical Laboratory Science, Doisy School of Allied Health Professions, Saint Louis University Health Sciences Center, 3437 Caroline St, St Louis, MO 63104-1111, USA. Randoltr@slu.edu
Abstract
DATA SYNTHESIS: Chronic myelocytic leukemia (CML) was initially described in 1845 and is considered one of the first leukemias discovered. Effective approaches to therapy were not instituted until arsenic was first administered in 1865. Since then, four major therapeutic milestones have been achieved; the development of alkylating agents like busulphan and 6-thioguanine in 1953, alpha interferon in 1983, bone marrow transplantation in 1986, and tyrosine kinase inhibitors in 1998. The discovery that the protein product of this fusion gene expresses constitutive tyrosine kinase activity prompted the synthesis of a designer drug, imatinib mesylate, which binds the fusion protein and neutralizes the tyrosine kinase activity. Molecular methods of detecting BCR-ABL transcripts are showing promise in confirming drug resistance and predicting patient outcomes in response to imatinib mesylate therapy. Evidence of drug resistance can guide physicians in selecting alternative therapeutic approaches early in the course of the disease to potentially rescue non responders. Although the success of clinical trials has been dramatic, drug resistance and disease relapse are issues to be considered. CONCLUSION: The discovery that the BCR/ABL fusion protein exhibits increased and constitutive tyrosine kinase activity led investigators to develop an inhibitor to this activity. The synthesis of imatinib mesylate, currently marketed as Gleevec(TM) or Glivec(R), is in stage III clinical trials and has proven to be the most successful antileukemic drug to date. As in CML, an understanding of the leukemogenic mechanisms involved in other leukemias will provide the groundwork for the development of therapeutic interventions tailored to the specific molecular defects identified, eventually rendering obsolete the shotgun approaches to massive cell killing produced by chemotherapy.
DATA SYNTHESIS: Chronic myelocytic leukemia (CML) was initially described in 1845 and is considered one of the first leukemias discovered. Effective approaches to therapy were not instituted until arsenic was first administered in 1865. Since then, four major therapeutic milestones have been achieved; the development of alkylating agents like busulphan and 6-thioguanine in 1953, alpha interferon in 1983, bone marrow transplantation in 1986, and tyrosine kinase inhibitors in 1998. The discovery that the protein product of this fusion gene expresses constitutive tyrosine kinase activity prompted the synthesis of a designer drug, imatinib mesylate, which binds the fusion protein and neutralizes the tyrosine kinase activity. Molecular methods of detecting BCR-ABL transcripts are showing promise in confirming drug resistance and predicting patient outcomes in response to imatinib mesylate therapy. Evidence of drug resistance can guide physicians in selecting alternative therapeutic approaches early in the course of the disease to potentially rescue non responders. Although the success of clinical trials has been dramatic, drug resistance and disease relapse are issues to be considered. CONCLUSION: The discovery that the BCR/ABL fusion protein exhibits increased and constitutive tyrosine kinase activity led investigators to develop an inhibitor to this activity. The synthesis of imatinib mesylate, currently marketed as Gleevec(TM) or Glivec(R), is in stage III clinical trials and has proven to be the most successful antileukemic drug to date. As in CML, an understanding of the leukemogenic mechanisms involved in other leukemias will provide the groundwork for the development of therapeutic interventions tailored to the specific molecular defects identified, eventually rendering obsolete the shotgun approaches to massive cell killing produced by chemotherapy.