Imatinib mesylate

A number of anticancer drugs have been developed that specifically target kinases known to be oncogenic. The first drug in this area is imatinib mesylate, which targets... 

The treatment of CML has experienced a dramatic change since the introduction of imatinib. Imatinib mesylate (STI-571 ... 

To demonstrate the utility of optophoresis in the preclinical stages of drug discovery, we screened several cell lines for their response to three standard chemotherapy drugs flu-darabine, vincristine, and Gleevec (imatinib mesylate, Novartis Pharmaceuticals, Basel, Switzerland) (Figure 7.6). To perform these measurements with the fast-scan technique, cells were suspended in a 9-mm-diameter well in a sample holder. The bottom surface of... 

Imatinib Mesylate (Gleevec) Tyrosine kinase inhibitor bcr-abl, c-kit Chronic myelogenous leukemia Hematologic and cytogenetic response rate. Phase III GIST ... 

The agents approved include Cefitinib (Iressa " ) (AstraZeneca), Imatinib mesylate (Cleevec) (Novartis Pharmaceuticals, East Hanover, NJ, U.S.A.), and Erlotinib (Tarceva ) (Cenentech). 

Cohen, M.H. et al.. Approval summary for Imatinib Mesylate capsules in the treatment of chronic myelogenous leukemia, Clin. Can. Res., 8, 935-942, 2002. 

Imatinib mesylate (Gleevec, Novartis) tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia (refer to Exhibit 7.3)... 

Exhibit 3.11 A Rational Approach to the Development of Imatinib Mesylate (Gleevec)... 

Imatinib mesylate (Gleevec, Novartis Glivec in countries other than the United States) is a drug for the treatment of chronic myeloid leukemia (CML). CML is a result of a chromosomal problem and gives rise to high levels of white blood cells. An enzyme called BCR-ABL is involved. The BCR-ABL gene encodes a protein with elevated tyrosine kinase activity (see Exhibit 7.3). 

Imatinib mesylate is a tyrosine kinase inhibitor (see Chapter 2 on receptors). It is used to block the growth of white blood cells. 

Imatinib mesylate is manufactured by Novartis. Clinical trials showed that patients had their white blood cells reduced substantially after being treated with Gleevec. 

In some circumstances, the FDA processes drug reviews under the accelerated scheme. This mechanism is to review and approve drugs speedily for cases where effective therapies are lacking or in situations of rare diseases. One of the fastest approval times to date is the case of imatinib mesylate (Gleevec, Novartis—Exhibit 7.3) for the treatment of chronic myeloid leukemia (CML) it was approved in less than 3 months after the filing of an NDA with the FDA. Another example is the new AIDS drug indinavir (Crixivan, Merck), which was approved in a mere 42 days. 

Imatinib mesylate (Gleevec, Novartis), zanamivir (Relenza, GlaxoSmithKline), and oseltamivir (Tamiflu, Roche) are examples of drugs (Exhibits 3.11 and 3.7) that show the successful contributions of rational drug design. For example, the X-ray structure of angiotensin converting enzyme (ACE) has been reported (see Exhibit 11.2), and this may pave the way for more effective ACE inhibitors to be developed for the treatment of hypertension and heart disorders. 

Cammenga, J., Horn, S., Bergholz, U., Sommer, G., Besmer, P., Fiedler, W. and Stocking, C. (2005) Extracellular KIT receptor mutants, commonly found in core binding factor AML, are constitutively active and respond to imatinib mesylate. Blood 106, 3958-3961. 

Demetri GD, von Meliren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tnmors. N Engl J Med 2002 347 472-80. 

In 1960, a minute acrocentric chromosome was noted in cells from seven patients with chronic myeloid leukemia (CML) (1). The subsequent identification of this abnormal chromosome 22, which came to be referred to as the Philadelphia chromosome, has become the basis for an explosion in knowledge over the past 40-plus years that culminated in the development of imatinib mesylate (IM), a highly effective targeted therapy of CML that is producing long-term disease control and a possible cure (2). 

Kantarjian H, Sawyers C, Hochhaus A et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. Y EnglJMed 2002 346 645-652. 

Shimizu T, Miyakawa Y, Iwata S et al. A novel mechanism for imatinib mesylate (STI571) resistance in CML cell line KT-1 role of TC-PTP in modulating signals downstream from the BCR-ABL fusion protein. Exp Hematol 2004 32 1057-1063. 

Ulmer T, Schaich M, Platzbecker U et al. P-glycoprotein-mediated drug efflux is a resistance mechanism of chronic myelogenous leukemia cells to treatment with imatinib mesylate. Leukemia 2004 18 401 08. 

Warmuth M, Simon N, Mitina O et al. Dual-specific SRC and ABL kinase inhibitors, PPl and CGP76030, inhibit growth and survival of cells expressing imatinib mesylate-resistant BCR-ABL kinases. Blood 2003 101 664-672. 

Donato N, Wu J, Kong LY et al. Constitutive activation of SRC-family kinases in chronic myelogenous leukemia patients resistant to imatinib mesylate in the absence of BCR-ABL mutations a rationale use of SRC/ABL dual kinase inhibitor-based therapy (Abstract 1087). B/oo<7 2005 106 316a. 

Melo JV, Chuah C. Resistance to imatinib mesylate in chronic myeloid leukaemia. Cancer... 

Corbin AS, La Rosee P, Stoffregen EP et al. Several BCR-ABL kinase domain mutants associated with imatinib mesylate resistanee remain sensitive to imatinib. B/ood2003 101 4611 614. 

Nicolini FE, Corm S, Le QH et al. Mutation status and elinieal outeome of 89 imatinib mesylate-resistant chronic myelogenous leukemia patients a retrospeetive analysis from the French intergroup of CML (Fi(phi)-LMC GROUP). Leukemia 2006 20 1061-1066. 

Jabbour E, Kantaqian H, Jones D et al. Frequeney and elinieal signifieanee of BCR-ABL mutations in patients with chronic myeloid leukemia treated with imatinib mesylate. Leukemia 2006 20 1767-1773. 

Kreuzer KA, Le Coutre P, Landt O et al. Pre-existence and evolution of imatinib mesylate-resistant clones in ehronie myelogenous leukemia detected by a PNA-based PCR clamping technique. Ann Hematol 2003 82 284-289. 

Kantarjian HM, Talpaz M, O Brien S et al. Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. Blood 2003 101 473 75. 

Kantarjian HM, Cortes JE, O Brien S et al. Long-term survival benefit and improved complete eytogenetie and molecular response rates with imatinib mesylate in Philadelphia chromosomepositive chronic-phase chronic myeloid leukemia after failure of interferon-alpha. Blood 2004 104 1979-1988. 

Liu NS, O Brien S. Spontaneous reversion from blast to ehronie phase after withdrawal of imatinib mesylate in a patient with ehronie myelogenous leukemia. LeukLymphoma 2002 43 2413-2415. Muller MC, Lahaye T, Hoehhaus A. [Resistanee to tumor speeifie therapy with imatinib by elonal seleetion of mutated Dtsch Med Wochenschr 2002 127 2205-2207. 

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