Use of Temozolomide in Aggressive Pituitary Tumors

Mohammed, Safraz; Kovács, Kálmán; Mason, Warren P.; Smyth, Harley S.; Cusimano, Michael D.

doi:10.1227/01.neu.0000339115.12803.4e

Cited by 79 publications

(68 citation statements)

References 17 publications

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“…These included tumor necrosis and hemorrhage, 15,23 tumor degenerative and cystic changes, 22 and tumor shrinkage. 2,10,11,14,[19][20][21]24 These changes could be observed as early as 2 months after the onset of temozolomide treatment.…”

Section: Morphologic Changesmentioning

confidence: 97%

“…Fully 10 more patients with pituitary adenomas have received treatment with temozolomide 2,10,11,14,19,20,22 (unpublished results), bringing the current total to 13 patients, including 9 men and 4 women ages 20 to 61 years (mean, 47.9 years) ( Table 2). Aside from 1 incidentally discovered tumor in a patient with concomitant glioblastoma multiforme, all tumors have been studied morphologically.…”

Section: Pituitary Adenomasmentioning

confidence: 99%

“…Two additional case reports of invasive, ACTH-producing adenomas with low-level MGMT expression also demonstrated the corresponding efficacy of temozolomide therapy. 2,20 Thus, determining the level of MGMT immunostaining appears to be useful for predicting the response of aggressive pituitary adenomas and carcinomas to temozolomide. 2 The reports of Kovacs et al 16 and McCormack et al 19 underscored the inverse relation between MGMT immunoexpression and the efficacy of temozolomide therapy, a relation that also has been noted in high-grade gliomas.…”

Section: Mgmt Immunoexpressionmentioning

confidence: 99%

“…2,20 Thus, determining the level of MGMT immunostaining appears to be useful for predicting the response of aggressive pituitary adenomas and carcinomas to temozolomide. 2 The reports of Kovacs et al 16 and McCormack et al 19 underscored the inverse relation between MGMT immunoexpression and the efficacy of temozolomide therapy, a relation that also has been noted in high-grade gliomas. 51,52 Whereas the standard method of evaluating MGMT status is the identification of promoter methylation, the detection of MGMT expression by immunohistochemistry presents an attractive alternative.…”

Section: Mgmt Immunoexpressionmentioning

confidence: 99%

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Treatment of pituitary neoplasms with temozolomide

Syro

Ortíz

Scheithauer

et al. 2010

Cancer

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Temozolomide, an orally administered alkylating agent, is used to treat malignant gliomas. Recent reports also have documented its efficacy in the treatment of pituitary adenomas and carcinomas. Temozolomide methylates DNA and thereby exhibits an antitumor effect. O 6 -methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme, removes alkylating adducts induced by temozolomide, counteracting its effects. The authors of this review conducted a Medline database search regarding temozolomide in the treatment of pituitary tumors. Demographic characteristics, tumor types, and therapeutic responses were noted in all patients. Data regarding MGMT immunoexpression, which was documented in some studies, were correlated with information regarding clinical and radiologic responses. To date, there have been 19 reported cases of adenohypophyseal tumors treated with temozolomide, including 13 adenomas and 6 carcinomas. Ten of those 13 adenomas responded favorably, and 2 nonresponsive tumors had highlevel MGMT immunoexpression. All 6 carcinomas responded to therapy, but data regarding MGMT expression were available for only 3 patients, and each had low MGMT expression. In 2 adenomas, morphologic studies were performed both before and after the patients received temozolomide. The responsive tumor had necrosis, hemorrhage, fibrosis, and neuronal differentiation. The nonresponsive tumor had no changes. There have been no reported complications attributable to temozolomide. The current results indicated that temozolomide is efficacious in the treatment of aggressive pituitary adenomas and pituitary carcinomas. Evidence indicated that low-level MGMT immunoexpression is correlated with a favorable response. A significant proportion of pituitary adenomas and carcinomas had low MGMT immunoexpression. Cancer 2011;117:454-62.

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Section: Morphologic Changesmentioning

confidence: 97%

Section: Pituitary Adenomasmentioning

confidence: 99%

Section: Mgmt Immunoexpressionmentioning

confidence: 99%

Section: Mgmt Immunoexpressionmentioning

confidence: 99%

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Treatment of pituitary neoplasms with temozolomide

Syro

Ortíz

Scheithauer

et al. 2010

Cancer

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“…In addition, TMZ clinical trials have been performed to test its activity against brain metastatic solid tumors, leukemia (8), pancreatic neuro endocrine tumors (9) and refractory pituitary adenomas (10)(11)(12)(13)(14). Two case studies related to gonadotroph adenoma patients report that their lesions decreased after TMZ therapy (15,16), and studies of TMZ on MMQ, GH3, and AtT20 cell lines suggested that this drug may have efficacy in pituitary adenoma cells (17 to attain biochemical control in a severe case of acromegaly (18).…”

Section: Introductionmentioning

confidence: 99%

Effect of temozolomide on cell viability in gonadotroph adenoma cell lines

Liu²,

Yao³

et al. 2011

Oncol Rep

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Abstract. Invasive pituitary adenomas are usually refractory to routine neurosurgery, radiosurgery or medications, and alternative therapies are needed. The effects of temozolomide (TMZ) on the inhibition of gonadotroph adenoma cell viability and hormone secretion were evaluated. Cell viability and IC 50 values were evaluated after αT3-1 cells were treated with TMZ (31.25-1000 µM) or vehicle for 0-72 h. Cell cycle changes and the extent of apoptosis were detected using flow cytometry, TUNEL and TEM. The molecular mechanism of TMZ action was investigated by the Caspase-Glo ® assay and immunoblotting. Gonadotropin secretion was assessed using an immunoassay system. TMZ dose-and time-dependently suppressed cell proliferation (P<0.01 vs. control, 250 µM, 24 h) and induced S-phase accumulation and G2/M-phase arrest (P<0.05 vs. control, 250 µM, 24 h). Early apoptotic cells increased following a 24-h TMZ incubation (P<0.001 vs. control, 250 µM), consistent with TEM and TUNEL detection that exhibited morphological features of apoptosis. TMZ (250 µM) increased the level of caspase-3/7 by 6-fold, caspase-9 by 7-fold and caspase-8 by 3-fold after a 24-h incubation, while it attenuated Bcl-2 expression (P<0.001 vs.control) and raised the proteolysis of PARP. Both FSH and LH levels were significantly decreased by TMZ (P<0.01 vs. control, 250 µM, 24 h). TMZ inhibited cell proliferation and hormone secretion, and induced cell cycle arrest and apoptotic cell death in gonadotroph adenoma cells via both death receptor and mitochondrial pathways, suggesting that it may represent a useful medical management strategy of invasive gonadotroph adenomas.

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