title: The role of imatinib mesylate (Glivec) for treatment of patients with malignant endocrine tumors positive for c-kit or PDGF-R.
abstract: Imatinib mesylate (IM), a small molecule that is a selective inhibitor of the ABL, platelet derived growth factor receptor (PDGFR-R) and stem cell ligand receptor (c-kit) tyrosine kinases (TK). IM was also found to inhibit the TK activity of BCR/ABL fusion protein produced in chronic myelogenous leukemia, with marked clinical activity against the disease. Since both PDGF-R and c-kit both having a putative role in tumorigenesis, we investigated the efficacy and safety of the use of IM in patients with endocrine tumors unresponsive to conventional therapies that expressed c-kit and/or PDGF-R (within the framework of a comprehensive phase II multi-center study of IM in patients with solid tumors). IM was initiated at a dose of 400 mg/day, with possible dose escalation within 1 week to 600 mg/day and an option to raise the dose to 800 mg/day in the event of progression and in the absence of safety concerns for a period of up to 12 months. Between September 2002 and July 2003, 15 adult patients with disseminated endocrine tumors were recruited as follows: medullary thyroid carcinoma (MTC, n = 6); adrenocortical carcinoma (ACC, n = 4); malignant pheochromocytoma (pheo, n = 2); carcinoid (non-secreting, n = 2), neuroendocrine tumor (NET, n = 1). No objective responses were observed. MTC--disease progression in 4 patients, and treatment discontinuation in 2 patients due to adverse events; ACC--disease progression in 3 patients, and treatment discontinuation in 1 patient due to severe psychiatric adverse event; Pheo--disease progression in 2 patients; Carcinoid--stable disease in 1 patient (6.5 months), and disease progression in 1 patient; NET--disease progression in 1 patient. IM does not appear to be useful for treatment of malignant endocrine tumors, also causing significant toxicity in this patient population.
authors.affiliation: Endocrinology and Metabolism Service, Department of Medicine, Hadassah University Hospital, P.O.B 12000, Jerusalem, Israel 91120. gross@vms.huji.ac.il
authors.forename: David J
authors.initials: DJ
authors.lastname: Gross
authors.forename: Gabriel
authors.initials: G
authors.lastname: Munter
authors.forename: Menachem
authors.initials: M
authors.lastname: Bitan
authors.forename: Tali
authors.initials: T
authors.lastname: Siegal
authors.forename: Alberto
authors.initials: A
authors.lastname: Gabizon
authors.forename: Ronny
authors.initials: R
authors.lastname: Weitzen
authors.forename: Ofer
authors.initials: O
authors.lastname: Merimsky
authors.forename: Aliza
authors.initials: A
authors.lastname: Ackerstein
authors.forename: Asher
authors.initials: A
authors.lastname: Salmon
authors.forename: Avishai
authors.initials: A
authors.lastname: Sella
authors.forename: Shimon
authors.initials: S
authors.lastname: Slavin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use* / Q000633:toxicity; D001549:Benzamides; D004701:Endocrine Gland Neoplasms / Q000737:chemistry / Q000188:drug therapy*; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000627:therapeutic use* / Q000633:toxicity; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use* / Q000633:toxicity; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis; D011743:Pyrimidines / Q000627:therapeutic use* / Q000633:toxicity; D017479:Receptors, Platelet-Derived Growth Factor / Q000032:analysis; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D017479:Receptors, Platelet-Derived Growth Factor