Imatinib (Gleevec, Novartis, Basel, Switzerland), formerly referredto as STI571, is an inhibitor of specific protein tyrosine kinasesthat was targeted to the platelet-derived growth factor (PDGF)receptor (Figure 1). It was found to inhibit the constitutivelyactive fusion product arising from the Philadelphia (Ph) chromosomeof chronic myelogenous leukemia (CML) and c-kit (CD117), whichis overexpressed in gastrointestinal stromal tumors. Studiesof imatinib in other tumors that express c-kit or the PDGF receptorare under way. Imatinib was approved by the Food and Drug Administrationin May 2001 for the treatment of CML that is refractory to . . . [Full Text of this Article]
Protein Kinases as Therapeutic Targets
Chronic Myelogenous Leukemia
Clinical Features
Pathogenesis
Rationale for the Development of Imatinib
Standard Treatment of CML and the Need for Better Therapy
Phase 1 Trials of Imatinib for CML
Chronic Phase
Blast Phase
Phase 2 Trials of Imatinib for CML
Resistance of CML to Imatinib
Unanswered Questions
Imatinib for Gastrointestinal Stromal Tumors
Imatinib for Other Leukemias and Solid Tumors
Conclusions
Source Information
From the Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, New York.
Park, I., Ryu, M.-H., Sym, S. J., Lee, S. S., Jang, G., Kim, T. W., Chang, H. M., Lee, J.-L., Lee, H., Kang, Y.-K.
(2008). Dose Escalation of Imatinib After Failure of Standard Dose in Korean Patients with Metastatic or Unresectable Gastrointestinal Stromal Tumor. Jpn J Clin Oncol
0: hyn134v1-6
[Abstract][Full Text]
Ma, S., Subramanian, R., Xu, Y., Schrag, M., Shou, M.
(2008). Structural Characterization of Novel Adenine Dinucleotide Phosphate Conjugates of Imatinib in Incubations with Rat and Human Liver Microsomes. Drug Metab. Dispos.
36: 2414-2418
[Abstract][Full Text]
Larmonier, N., Janikashvili, N., LaCasse, C. J., Larmonier, C. B., Cantrell, J., Situ, E., Lundeen, T., Bonnotte, B., Katsanis, E.
(2008). Imatinib Mesylate Inhibits CD4+CD25+ Regulatory T Cell Activity and Enhances Active Immunotherapy against BCR-ABL- Tumors. J. Immunol.
181: 6955-6963
[Abstract][Full Text]
Lozano, E, Segarra, M, Garcia-Martinez, A, Hernandez-Rodriguez, J, Cid, M C
(2008). Imatinib mesylate inhibits in vitro and ex vivo biological responses related to vascular occlusion in giant cell arteritis. Ann Rheum Dis
67: 1581-1588
[Abstract][Full Text]
Kimura, S., Egashira, K., Nakano, K., Iwata, E., Miyagawa, M., Tsujimoto, H., Hara, K., Kawashima, Y., Tominaga, R., Sunagawa, K.
(2008). Local Delivery of Imatinib Mesylate (STI571)-Incorporated Nanoparticle Ex Vivo Suppresses Vein Graft Neointima Formation. Circulation
118: S65-S70
[Abstract][Full Text]
Sfikakis, P. P., Gorgoulis, V. G., Katsiari, C. G., Evangelou, K., Kostopoulos, C., Black, C. M.
(2008). Imatinib for the treatment of refractory, diffuse systemic sclerosis. Rheumatology (Oxford)
47: 735-737
[Full Text]
Weichsel, R., Dix, C., Wooldridge, L., Clement, M., Fenton-May, A., Sewell, A. K., Zezula, J., Greiner, E., Gostick, E., Price, D. A., Einsele, H., Seggewiss, R.
(2008). Profound Inhibition of Antigen-Specific T-Cell Effector Functions by Dasatinib. Clin. Cancer Res.
14: 2484-2491
[Abstract][Full Text]
Perik, P. J., Rikhof, B., de Jong, F. A., Verweij, J., Gietema, J. A., van der Graaf, W. T. A.
(2008). Results of plasma N-terminal pro B-type natriuretic peptide and cardiac troponin monitoring in GIST patients do not support the existence of imatinib-induced cardiotoxicity. Ann Oncol
19: 359-361
[Abstract][Full Text]
Marshall, H. M, Hammond, J. M
(2008). Treatment Options in Imatinib-Resistant Chronic Myelogenous Leukemia. The Annals of Pharmacotherapy
42: 259-264
[Abstract][Full Text]
Cassier, P. A., Dufresne, A., Blay, J.-Y.
(2008). Controversies in the Adjuvant Treatment of Gastrointestinal Stromal Tumors (GIST) with Imatinib. Am Soc Clin Oncol Ed Book
2008: 524-528
[Abstract][Full Text]
Barry, R. J, de Moura, L. R, Marshall, J.-C., Fernandes, B. F, Orellana, M. E., Antecka, E., Martins, C., Burnier, M. N
(2007). Expression of C-kit in retinoblastoma: a potential therapeutic target. Br. J. Ophthalmol.
91: 1532-1536
[Abstract][Full Text]
Frank-Raue, K., Fabel, M., Delorme, S., Haberkorn, U., Raue, F.
(2007). Efficacy of imatinib mesylate in advanced medullary thyroid carcinoma. Eur J Endocrinol
157: 215-220
[Abstract][Full Text]
de Borst, M. H., Diks, S. H., Bolbrinker, J., Schellings, M. W., van Dalen, M. B. A., Peppelenbosch, M. P., Kreutz, R., Pinto, Y. M., Navis, G., van Goor, H.
(2007). Profiling of the renal kinome: a novel tool to identify protein kinases involved in angiotensin II-dependent hypertensive renal damage. Am. J. Physiol. Renal Physiol.
293: F428-F437
[Abstract][Full Text]
Picard, S., Titier, K., Etienne, G., Teilhet, E., Ducint, D., Bernard, M.-A., Lassalle, R., Marit, G., Reiffers, J., Begaud, B., Moore, N., Molimard, M., Mahon, F.-X.
(2007). Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood
109: 3496-3499
[Abstract][Full Text]
Pan, J., Quintas-Cardama, A., Kantarjian, H. M., Akin, C., Manshouri, T., Lamb, P., Cortes, J. E., Tefferi, A., Giles, F. J., Verstovsek, S.
(2007). EXEL-0862, a novel tyrosine kinase inhibitor, induces apoptosis in vitro and ex vivo in human mast cells expressing the KIT D816V mutation. Blood
109: 315-322
[Abstract][Full Text]
Lassau, N., Lamuraglia, M., Chami, L., Leclere, J., Bonvalot, S., Terrier, P., Roche, A., Le Cesne, A.
(2006). Gastrointestinal stromal tumors treated with imatinib: monitoring response with contrast-enhanced sonography.. Am. J. Roentgenol.
187: 1267-1273
[Abstract][Full Text]
Baccarani, M., Saglio, G., Goldman, J., Hochhaus, A., Simonsson, B., Appelbaum, F., Apperley, J., Cervantes, F., Cortes, J., Deininger, M., Gratwohl, A., Guilhot, F., Horowitz, M., Hughes, T., Kantarjian, H., Larson, R., Niederwieser, D., Silver, R., Hehlmann, R.
(2006). Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood
108: 1809-1820
[Abstract][Full Text]
Matsukuma, S., Yoshihara, M., Kasai, F., Kato, A., Yoshida, A., Akaike, M., Kobayashi, O., Nakayama, H., Sakuma, Y., Yoshida, T., Kameda, Y., Tsuchiya, E., Miyagi, Y.
(2006). Rapid and Simple Detection of Hot Spot Point Mutations of Epidermal Growth Factor Receptor, BRAF, and NRAS in Cancers Using the Loop-Hybrid Mobility Shift Assay. J. Mol. Diagn.
8: 504-512
[Abstract][Full Text]
Folli, F., Galimberti, G., Pastore, M., Davalli, A. M., Bosi, E.
(2006). Paraneoplastic insulin resistance syndrome in advanced aggressive fibromatosis (desmoid tumor) treated by imatinib mesylate.. Diabetes Care
29: 2178-2180
[Full Text]
Ishikubo, T., Akagi, K., Kurosumi, M., Yamaguchi, K., Fujimoto, T., Sakamoto, H., Tanaka, Y., Ochiai, A.
(2006). Immunohistochemical and Mutational Analysis of c-kit in Gastrointestinal Neuroendocrine Cell Carcinoma. Jpn J Clin Oncol
36: 494-498
[Abstract][Full Text]
Schellings, M. W.M., Baumann, M., van Leeuwen, R. E.W., Duisters, R. F.J.J., Janssen, S. H.P., Schroen, B., Peutz-Kootstra, C. J., Heymans, S., Pinto, Y. M.
(2006). Imatinib Attenuates End-Organ Damage in Hypertensive Homozygous TGR(mRen2)27 Rats. Hypertension
47: 467-474
[Abstract][Full Text]
Aloisi, A., Di Gregorio, S., Stagno, F., Guglielmo, P., Mannino, F., Sormani, M. P., Bruzzi, P., Gambacorti-Passerini, C., Saglio, G., Venuta, S., Giustolisi, R., Messina, A., Vigneri, P.
(2006). BCR-ABL nuclear entrapment kills human CML cells: ex vivo study on 35 patients with the combination of imatinib mesylate and leptomycin B. Blood
107: 1591-1598
[Abstract][Full Text]
Carter, B. Z., Mak, D. H., Schober, W. D., Cabreira-Hansen, M., Beran, M., McQueen, T., Chen, W., Andreeff, M.
(2006). Regulation of survivin expression through Bcr-Abl/MAPK cascade: targeting survivin overcomes imatinib resistance and increases imatinib sensitivity in imatinib-responsive CML cells. Blood
107: 1555-1563
[Abstract][Full Text]
Du, Y., Wang, K., Fang, H., Li, J., Xiao, D., Zheng, P., Chen, Y., Fan, H., Pan, X., Zhao, C., Zhang, Q., Imbeaud, S., Graudens, E., Eveno, E., Auffray, C., Chen, S., Chen, Z., Zhang, J.
(2006). Coordination of intrinsic, extrinsic, and endoplasmic reticulum-mediated apoptosis by imatinib mesylate combined with arsenic trioxide in chronic myeloid leukemia. Blood
107: 1582-1590
[Abstract][Full Text]
Zohlnhofer, D., Hausleiter, J., Kastrati, A., Mehilli, J., Goos, C., Schuhlen, H., Pache, J., Pogatsa-Murray, G., Heemann, U., Dirschinger, J., Schomig, A.
(2005). A Randomized, Double-Blind, Placebo-Controlled Trial on Restenosis Prevention by the Receptor Tyrosine Kinase Inhibitor Imatinib. J Am Coll Cardiol
46: 1999-2003
[Abstract][Full Text]
Rossi, G., Cavazza, A., Marchioni, A., Longo, L., Migaldi, M., Sartori, G., Bigiani, N., Schirosi, L., Casali, C., Morandi, U., Facciolongo, N., Maiorana, A., Bavieri, M., Fabbri, L. M., Brambilla, E.
(2005). Role of Chemotherapy and the Receptor Tyrosine Kinases KIT, PDGFR{alpha}, PDGFR{beta}, and Met in Large-Cell Neuroendocrine Carcinoma of the Lung. JCO
23: 8774-8785
[Abstract][Full Text]
Arora, A., Scholar, E. M.
(2005). Role of Tyrosine Kinase Inhibitors in Cancer Therapy. J. Pharmacol. Exp. Ther.
315: 971-979
[Abstract][Full Text]
Ginsburg, G. S., Konstance, R. P., Allsbrook, J. S., Schulman, K. A.
(2005). Implications of Pharmacogenomics for Drug Development and Clinical Practice. Arch Intern Med
165: 2331-2336
[Abstract][Full Text]
Pricl, S., Fermeglia, M., Ferrone, M., Tamborini, E.
(2005). T315I-mutated Bcr-Abl in chronic myeloid leukemia and imatinib: insights from a computational study. Molecular Cancer Therapeutics
4: 1167-1174
[Abstract][Full Text]
Andreu, E. J., Lledo, E., Poch, E., Ivorra, C., Albero, M. P., Martinez-Climent, J. A., Montiel-Duarte, C., Rifon, J., Perez-Calvo, J., Arbona, C., Prosper, F., Perez-Roger, I.
(2005). BCR-ABL Induces the Expression of Skp2 through the PI3K Pathway to Promote p27Kip1 Degradation and Proliferation of Chronic Myelogenous Leukemia Cells. Cancer Res.
65: 3264-3272
[Abstract][Full Text]
Gupta, K, Zhang, J
(2005). Angiogenesis: a curse or cure?. Postgrad. Med. J.
81: 236-242
[Abstract][Full Text]
Jayson, G.C., Parker, G.J.M., Mullamitha, S., Valle, J.W., Saunders, M., Broughton, L., Lawrance, J., Carrington, B., Roberts, C., Issa, B., Buckley, D.L., Cheung, S., Davies, K., Watson, Y., Zinkewich-Peotti, K., Rolfe, L., Jackson, A.
(2005). Blockade of Platelet-Derived Growth Factor Receptor-Beta by CDP860, a Humanized, PEGylated di-Fab', Leads to Fluid Accumulation and Is Associated With Increased Tumor Vascularized Volume. JCO
23: 973-981
[Abstract][Full Text]
Stone, R. M., DeAngelo, D. J., Klimek, V., Galinsky, I., Estey, E., Nimer, S. D., Grandin, W., Lebwohl, D., Wang, Y., Cohen, P., Fox, E. A., Neuberg, D., Clark, J., Gilliland, D. G., Griffin, J. D.
(2005). Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood
105: 54-60
[Abstract][Full Text]
Yin, T., Wu, Y.-L., Sun, H.-P., Sun, G.-L., Du, Y.-Z., Wang, K.-K., Zhang, J., Chen, G.-Q., Chen, S.-J., Chen, Z.
(2004). Combined effects of As4S4 and imatinib on chronic myeloid leukemia cells and BCR-ABL oncoprotein. Blood
104: 4219-4225
[Abstract][Full Text]
Baccarani, M., Martinelli, G., Rosti, G., Trabacchi, E., Testoni, N., Bassi, S., Amabile, M., Soverini, S., Castagnetti, F., Cilloni, D., Izzo, B., de Vivo, A., Messa, E., Bonifazi, F., Poerio, A., Luatti, S., Giugliano, E., Alberti, D., Fincato, G., Russo, D., Pane, F., Saglio, G., for the GIMEMA Working Party on Chronic Myeloid Le,
(2004). Imatinib and pegylated human recombinant interferon-{alpha}2b in early chronic-phase chronic myeloid leukemia. Blood
104: 4245-4251
[Abstract][Full Text]
Champagne, M. A., Capdeville, R., Krailo, M., Qu, W., Peng, B., Rosamilia, M., Therrien, M., Zoellner, U., Blaney, S. M., Bernstein, M.
(2004). Imatinib mesylate (STI571) for treatment of children with Philadelphia chromosome-positive leukemia: results from a Children's Oncology Group phase 1 study. Blood
104: 2655-2660
[Abstract][Full Text]
Demetri, G. D., Titton, R. L., Ryan, D. P., Fletcher, C. D.M.
(2004). Case 32-2004 - A 68-Year-Old Man with a Large Retroperitoneal Mass. NEJM
351: 1779-1787
[Full Text]
Dietz, A. B., Souan, L., Knutson, G. J., Bulur, P. A., Litzow, M. R., Vuk-Pavlovic, S.
(2004). Imatinib mesylate inhibits T-cell proliferation in vitro and delayed-type hypersensitivity in vivo. Blood
104: 1094-1099
[Abstract][Full Text]
Guilhot, F.
(2004). Indications for Imatinib Mesylate Therapy and Clinical Management. The Oncologist
9: 271-281
[Abstract][Full Text]
Chu, S., Holtz, M., Gupta, M., Bhatia, R.
(2004). BCR/ABL kinase inhibition by imatinib mesylate enhances MAP kinase activity in chronic myelogenous leukemia CD34+ cells. Blood
103: 3167-3174
[Abstract][Full Text]
Dowlati, A., Nethery, D., Kern, J. A.
(2004). Combined inhibition of epidermal growth factor receptor and JAK/STAT pathways results in greater growth inhibition in vitro than single agent therapy. Molecular Cancer Therapeutics
3: 459-463
[Abstract][Full Text]
Bagrintseva, K., Schwab, R., Kohl, T. M., Schnittger, S., Eichenlaub, S., Ellwart, J. W., Hiddemann, W., Spiekermann, K.
(2004). Mutations in the tyrosine kinase domain of FLT3 define a new molecular mechanism of acquired drug resistance to PTK inhibitors in FLT3-ITD-transformed hematopoietic cells. Blood
103: 2266-2275
[Abstract][Full Text]
Gonzalez, I., Andreu, E. J., Panizo, A., Inoges, S., Fontalba, A., Fernandez-Luna, J. L., Gaboli, M., Sierrasesumaga, L., Martin-Algarra, S., Pardo, J., Prosper, F., de Alava, E.
(2004). Imatinib Inhibits Proliferation of Ewing Tumor Cells Mediated by the Stem Cell Factor/KIT Receptor Pathway, and Sensitizes Cells to Vincristine and Doxorubicin-Induced Apoptosis. Clin. Cancer Res.
10: 751-761
[Abstract][Full Text]
Johnson, M. D., Aulino, J. P., Jagasia, M., Mawn, L. A.
(2004). Erdheim-Chester Disease Mimicking Multiple Meningiomas Syndrome. Am. J. Neuroradiol.
25: 134-137
[Abstract][Full Text]
Herbst, R. S., Bunn, P. A. Jr.
(2003). Targeting the Epidermal Growth Factor Receptor in Non-Small Cell Lung Cancer. Clin. Cancer Res.
9: 5813-5824
[Abstract][Full Text]
Vlahovic, G., Crawford, J.
(2003). Activation of Tyrosine Kinases in Cancer. The Oncologist
8: 531-538
[Abstract][Full Text]
Nimmanapalli, R., Bali, P., O'Bryan, E., Fuino, L., Guo, F., Wu, J., Houghton, P., Bhalla, K.
(2003). Arsenic Trioxide Inhibits Translation of mRNA of bcr-abl, Resulting in Attenuation of Bcr-Abl Levels and Apoptosis of Human Leukemia Cells. Cancer Res.
63: 7950-7958
[Abstract][Full Text]
Kris, M. G., Natale, R. B., Herbst, R. S., Lynch, T. J. Jr, Prager, D., Belani, C. P., Schiller, J. H., Kelly, K., Spiridonidis, H., Sandler, A., Albain, K. S., Cella, D., Wolf, M. K., Averbuch, S. D., Ochs, J. J., Kay, A. C.
(2003). Efficacy of Gefitinib, an Inhibitor of the Epidermal Growth Factor Receptor Tyrosine Kinase, in Symptomatic Patients With Non-Small Cell Lung Cancer: A Randomized Trial. JAMA
290: 2149-2158
[Abstract][Full Text]
Goldman, J. M., Melo, J. V.
(2003). Chronic Myeloid Leukemia -- Advances in Biology and New Approaches to Treatment. NEJM
349: 1451-1464
[Full Text]
Tauchi, T., Sumi, M., Nakajima, A., Sashida, G., Shimamoto, T., Ohyashiki, K.
(2003). BCL-2 Antisense Oligonucleotide Genasense Is Active against Imatinib-resistant BCR-ABL-positive Cells. Clin. Cancer Res.
9: 4267-4273
[Abstract][Full Text]
Rosado, M. F., Donna, E., Ahn, Y. S.
(2003). Challenging Problems in Advanced Malignancy: CASE 3. IMATINIB MESYLATE-INDUCED INTERSTITIAL PNEUMONITIS. JCO
21: 3171-3173
[Full Text]
Goetz, M. P., Toft, D. O., Ames, M. M., Erlichman, C.
(2003). The Hsp90 chaperone complex as a novel target for cancer therapy. Ann Oncol
14: 1169-1176
[Abstract][Full Text]
Hahn, E. A., Glendenning, G. A., Sorensen, M. V., Hudgens, S. A., Druker, B. J., Guilhot, F., Larson, R. A., O'Brien, S. G., Dobrez, D. G., Hensley, M. L., Cella, D.
(2003). Quality of Life in Patients With Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia on Imatinib Versus Interferon Alfa Plus Low-Dose Cytarabine: Results From the IRIS Study. JCO
21: 2138-2146
[Abstract][Full Text]
Scotlandi, K., Manara, M. C., Strammiello, R., Landuzzi, L., Benini, S., Perdichizzi, S., Serra, M., Astolfi, A., Nicoletti, G., Lollini, P.-L., Bertoni, F., Nanni, P., Picci, P.
(2003). c-kit Receptor Expression in Ewing's Sarcoma: Lack of Prognostic Value but Therapeutic Targeting Opportunities in Appropriate Conditions. JCO
21: 1952-1960
[Abstract][Full Text]
Wang, Z.-Y., Zhang, Q., Wilson, J., Ratajczak, M. Z., Wasik, M. A.
(2003). Detection of Protein Tyrosine-Kinase (PTK) Gene Expression Pattern in Normal and Malignant T Lymphocytes by Combined PTK-Specific Polymerase Chain Reaction and Parallel Denaturing Gradient Gel Electrophoresis. J. Mol. Diagn.
5: 113-120
[Abstract][Full Text]
Nimmanapalli, R., Fuino, L., Stobaugh, C., Richon, V., Bhalla, K.
(2003). Cotreatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) enhances imatinib-induced apoptosis of Bcr-Abl-positive human acute leukemia cells. Blood
101: 3236-3239
[Abstract][Full Text]
Sanchez-Gonzalez, B., Pascual-Ramirez, J. C., Fernandez-Abellan, P., Belinchon-Romero, I., Rivas, C., Vegara-Aguilera, G.
(2003). Severe skin reaction to imatinib in a case of Philadelphia-positive acute lymphoblastic leukemia. Blood
101: 2446-2446
[Full Text]
Spiekermann, K., Dirschinger, R. J., Schwab, R., Bagrintseva, K., Faber, F., Buske, C., Schnittger, S., Kelly, L. M., Gilliland, D. G., Hiddemann, W.
(2003). The protein tyrosine kinase inhibitor SU5614 inhibits FLT3 and induces growth arrest and apoptosis in AML-derived cell lines expressing a constitutively activated FLT3. Blood
101: 1494-1504
[Abstract][Full Text]
Ramar, K., Potti, A., Mehdi, S. A.
(2003). Uncommon Syndromes and Treatment Manifestations of Malignancy: Case 4. Periorbital Edema and Imatinib Mesylate Therapy for Chronic Myelogenous Leukemia. JCO
21: 172-173
[Full Text]
Nimmanapalli, R., O'Bryan, E., Huang, M., Bali, P., Burnette, P. K., Loughran, T., Tepperberg, J., Jove, R., Bhalla, K.
(2002). Molecular Characterization and Sensitivity of STI-571 (Imatinib Mesylate, Gleevec)-resistant, Bcr-Abl-positive, Human Acute Leukemia Cells to SRC Kinase Inhibitor PD180970 and 17-Allylamino-17-demethoxygeldanamycin. Cancer Res.
62: 5761-5769
[Abstract][Full Text]
Bergeron, A., Bergot, E., Vilela, G., Ades, L., Devergie, A., Esperou, H., Socie, G., Calvo, F., Gluckman, E., Ribaud, P., Rousselot, Ph., Tazi, A.
(2002). Hypersensitivity Pneumonitis Related to Imatinib Mesylate. JCO
20: 4271-4272
[Full Text]
Luzzatto, L., Melo, J. V.
(2002). Acquired resistance to imatinib mesylate: selection for pre-existing mutant cells. Blood
100: 1105-1106
[Full Text]
Boros, L. G., Lee, W.-N. P., Cascante, M.
(2002). Imatinib and Chronic-Phase Leukemias. NEJM
347: 67-68
[Full Text]
McLeod, H. L.
(2002). Genetic Strategies to Individualize Supportive Care. JCO
20: 2765-2767
[Full Text]
(2002). Imatinib Mesylate Efficacy in CML Confirmed. JWatch General
2002: 6-6
[Full Text]
Previous
