Gastrointestinal stromal tumor treatment

Identification of patients who would not have otherwise qualified by virtue of a novel test, as has been the case for the use of imatinib in gastrointestinal stromal tumors that express a mutated KIT receptor, and increased treatment duration and compliance linked to prolongation of survival or efficacy in the adjuvant setting. In the final analysis, a significant clinical benefit can be expected to lead to higher adoption rates. 

Desai J, Yassa L, Marqusee E, George S, Frates MC, Chen MH, Morgan JA, Dychter SS, Larsen PR, Demetri GD, Alexander EK. Hypothyroidism after suni-tinib treatment for patients with gastrointestinal stromal tumors. Ann Intern Med 2006 145 660-4. 

Imatinib is administered orally and is well absorbed it is highly protein-bound in plasma. The drug is metabolized in the liver, and elimination of metabolites occurs mainly in feces via biliary excretion. This agent is approved for use as first-line therapy in chronic phase CML, in blast crisis, and as second-line therapy for chronic phase CML that has progressed on prior interferon- therapy. Imatinib is effective also for treatment of gastrointestinal stromal tumors expressing the c-kit tyrosine kinase. Dosage and toxicities are listed in Table 55-6. 

In summary, sunitinib maleate (1) is a multitargeted receptor tyrosine kinase inhibitor with potent anti-angiogenic and antitumor activity. It is approved for the treatment of advanced renal cell carcinoma and gastrointestinal stromal tumors, and is currently undergoing clinical trials for a number of additional malignancies. The discovery synthesis of 1 along with its process development approaches were described in this chapter. 

Goodman VL, Rock EP, Dagher R, et al. Approval summary Sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. Clin Cancer Res. 2007 13(5) 1367-1373. 

Croom KF, Perry CM. Imatinib mesylate in the treatment of gastrointestinal stromal tumors. Drugs 2003 63 513-522. 

Imatinib is a protein-tyrosine-kinase inhibitor. Imatinib inhibits proliferation and induces apoptosis in BCR-ABL positive cell lines as well as fresh leukemic cells from Philadelphia chromosome-positive (Ph-r) chronic myeloid leukemia (CML). Imatinib inhibits tumor growth of BCR-ABL transfected murine myeloid cells and BCR-ABL positive leukemia lines derived from CML patients in blast crisis. It also inhibits the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-Kit, and inhibits PDGF- and SCF-mediated cellular events. It is indicated in the treatment of newly diagnosed adult patients with Ph-t CML in chronic phase patients with Ph-t CML in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha treatment children with Ph-t chronic phase CML whose disease has recurred after stem cell transplant or who are resistant to interferon-alpha therapy and treatment of gastrointestinal stromal tumors (GIST). 

Imatinib mesylate (Gleevee, A -(4-methyl-3-(4-(pyridin-3-yl)-pyrimidin-2-ylamino) phenyl)-4-((4-methyl piperazin-l-yl)methyl) benzamide methane-sulfonate, STI571) is known as an inhibitor of tyrosine kinases and is used for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. It was developed by Novartis Pharma AG and is a 2-phenylamino-pyrimidine derivative. 

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