STI571: a paradigm of new agents for cancer therapeutics.

STI571 exemplifies the successful development of a rationally designed, molecularly targeted therapy for the treatment of a specific cancer. This article reviews the identification of Bcr-Abl as a therapeutic target in chronic myelogenous leukemia and the steps in the development of an agent to specifically inactivate this abnormality. Issues related to clinical trials of molecularly targeted agents are discussed, including dose selection, optimizing therapy, and predicting response, as are possible mechanisms of resistance to STI571. Lastly, the potential use of STI571 in other malignancies and the translation of this paradigm to other malignancies are explored.

[1]  J. Griffin,et al.  Mechanism of resistance to the ABL tyrosine kinase inhibitor STI571 in BCR/ABL-transformed hematopoietic cell lines. , 2000, Blood.

[2]  Susan M. Watanabe,et al.  An alteration of the human c-abl protein in K562 leukemia cells unmasks associated tyrosine kinase activity , 1984, Cell.

[3]  C. Heldin,et al.  Involvement of platelet-derived growth factor in disease: development of specific antagonists. , 2001, Advances in cancer research.

[4]  Todd,et al.  Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning , 2002, Nature Medicine.

[5]  M. Varella‐Garcia,et al.  Induction of resistance to the Abelson inhibitor STI571 in human leukemic cells through gene amplification. , 2000, Blood.

[6]  S. Hirota,et al.  Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. , 1998, Science.

[7]  C. Sawyers.  Chronic myeloid leukemia. , 1999, The New England journal of medicine.

[8]  K. Kolibaba,et al.  Efficacy of STI571, an abl tyrosine kinase inhibitor, in conjunction with other antileukemic agents against bcr-abl-positive cells. , 2000, Blood.

[9]  J. Melo,et al.  The molecular biology of chronic myeloid leukemia. , 2000, Blood.

[10]  R. Davis,et al.  Activation of the c-abl oncogene by viral transduction or chromosomal translocation generates altered c-abl proteins with similar in vitro kinase properties , 1985, Molecular and cellular biology.

[11]  A. Levitzki,et al.  Blocking of EGF-dependent cell proliferation by EGF receptor kinase inhibitors , 1988, Science.

[12]  Jürg Zimmermann,et al.  Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr–Abl positive cells , 1996, Nature Medicine.

[13]  A. Ho,et al.  Favorable therapeutic index of a p210BCR-ABL-specific tyrosine kinase inhibitor; activity on lineage-committed and primitive chronic myelogenous leukemia progenitors , 1999, Cancer Chemotherapy and Pharmacology.

[14]  B. Druker,et al.  Chronic myeloid leukemia: current treatment options. , 2001, Blood.

[15]  M. Carroll,et al.  CGP 57148, a tyrosine kinase inhibitor, inhibits the growth of cells expressing BCR-ABL, TEL-ABL, and TEL-PDGFR fusion proteins. , 1997, Blood.

[16]  B. Druker,et al.  Lessons learned from the development of an abl tyrosine kinase inhibitor for chronic myelogenous leukemia. , 2000, The Journal of clinical investigation.

[17]  Ash A. Alizadeh,et al.  Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling , 2000, Nature.

[18]  N. Rosenberg,et al.  The viral and cellular forms of the Abelson (abl) oncogene. , 1988, Advances in virus research.

[19]  J. Spivak,et al.  Commentary on and reprint of Nowell PC, Hungerford DA, A minute chromosome in human chronic granulocytic leukemia, in Science (1960) 132:1497 , 2000 .

[20]  M. Greaves,et al.  ts BCR-ABL kinase activation confers increased resistance to genotoxic damage via cell cycle block. , 1996, Oncogene.

[21]  S. Hirota,et al.  Familial gastrointestinal stromal tumours with germline mutation of the KIT gene , 1998, Nature Genetics.

[22]  B. Zehnbauer,et al.  Inhibition of apoptosis by BCR-ABL in chronic myeloid leukemia. , 1994, Blood.

[23]  J. Hasford,et al.  A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group. , 1998, Journal of the National Cancer Institute.

[24]  P. N. Rao,et al.  Clinical Resistance to STI-571 Cancer Therapy Caused by BCR-ABL Gene Mutation or Amplification , 2001, Science.

[25]  G. Jenster,et al.  Acute leukaemia in bcr/abl transgenic mice , 1990, Nature.

[26]  E. Buchdunger,et al.  In vivo eradication of human BCR/ABL-positive leukemia cells with an ABL kinase inhibitor. , 1999, Journal of the National Cancer Institute.

[27]  C. Sawyers,et al.  Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. , 2001, The New England journal of medicine.

[28]  R. Salgia,et al.  Growth inhibition and modulation of kinase pathways of small cell lung cancer cell lines by the novel tyrosine kinase inhibitor STI 571 , 2000, Oncogene.

[29]  P. Black,et al.  Intracranial inhibition of platelet-derived growth factor-mediated glioblastoma cell growth by an orally active kinase inhibitor of the 2-phenylaminopyrimidine class. , 2000, Cancer research.

[30]  C. Sawyers,et al.  Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. , 2001, The New England journal of medicine.

[31]  G. Daley,et al.  Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. , 1990, Science.

[32]  K. Kolibaba,et al.  Protein tyrosine kinases and cancer. , 1997, Biochimica et biophysica acta.

[33]  G. Daley,et al.  The chronic myelogenous leukemia-specific P210 protein is the product of the bcr/abl hybrid gene. , 1986, Science.

[34]  D. Tuveson,et al.  Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. , 2001, The New England journal of medicine.

[35]  J Hermans,et al.  Risk assessment for patients with chronic myeloid leukaemia before allogeneic blood or marrow transplantation , 1998, The Lancet.

[36]  Z. Estrov,et al.  Chronic Myelogenous Leukemia: Biology and Therapy , 1999, Annals of Internal Medicine.

[37]  B. Druker,et al.  Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. , 2000, The Journal of pharmacology and experimental therapeutics.

[38]  B. Druker,et al.  Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. , 2000, Blood.

[39]  N. Rosenberg,et al.  Induction of a chronic myelogenous leukemia-like syndrome in mice with v-abl and BCR/ABL. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[40]  M. Zucchetti,et al.  Role of (cid:1) 1 Acid Glycoprotein in the In Vivo Resistance of Human BCR-ABL + Leukemic Cells to the Abl Inhibitor STI571 , 2000 .

[41]  J. Melo,et al.  Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance. , 2000, Blood.

[42]  D. Tenen,et al.  Reversibility of acute B-cell leukaemia induced by BCR–ABL1 , 2000, Nature Genetics.

[43]  Z. Estrov,et al.  Selective inhibition of cell proliferation and BCR-ABL phosphorylation in acute lymphoblastic leukemia cells expressing Mr 190,000 BCR-ABL protein by a tyrosine kinase inhibitor (CGP-57148). , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.

[44]  M. Heinrich,et al.  STI 571 inhibits the kinase activity of wild type and juxtamembrane C-kit mutants but not the exon 17 D816V mutation associated with mastocytosis , 2000 .

[45]  M. Tomasson,et al.  TEL/PDGFβR Induces Hematologic Malignancies in Mice That Respond to a Specific Tyrosine Kinase Inhibitor , 1999 .

[46]  J. Stephenson,et al.  A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukaemia , 1982, Nature.

[47]  S. Honsawek,et al.  The selective tyrosine kinase inhibitor STI571 inhibits small cell lung cancer growth. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[48]  Todd R. Golub,et al.  Fusion of PDGF receptor β to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation , 1994, Cell.

[49]  S. Hirota,et al.  Biological and clinical review of stromal tumors in the gastrointestinal tract. , 2000, Histology and histopathology.

[50]  T. Hunter,et al.  The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. , 1988, Science.

[51]  O. Witte,et al.  Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. , 1990, Science.

[52]  J. Rowley.  A New Consistent Chromosomal Abnormality in Chronic Myelogenous Leukaemia identified by Quinacrine Fluorescence and Giemsa Staining , 1973, Nature.

[53]  E. Canaani,et al.  Fused transcript of abl and bcr genes in chronic myelogenous leukaemia , 1985, Nature.

[54]  J. Melo,et al.  The tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of BCR-ABL-positive cells. , 1997, Blood.

[55]  J. Fletcher,et al.  KIT extracellular and kinase domain mutations in gastrointestinal stromal tumors. , 2000, The American journal of pathology.