scholarly journals Temozolomide in the Treatment of Aggressive Pituitary Tumors—An Overview of Existing Knowledge and Future Perspectives

2012 ◽  
Vol 08 (02) ◽  
pp. 112
Author(s):  
Ann McCormack ◽  
Keyword(s):  
Dna Methyltransferase ◽  
Treatment Algorithm ◽  
Pituitary Tumors ◽  
Methylguanine Dna Methyltransferase ◽  
Pituitary Tumorigenesis ◽  
Significant Efficacy ◽  
Primary Determinant ◽  
Acth Secreting ◽  
Term Data

The management of aggressive pituitary tumors remains a challenge, however, the recent identification of temozolomide as a chemotherapeutic agent with significant efficacy against these tumors has heralded a new therapeutic era. There has been an exponential growth in the international experience with temozolomide over the past five years, now totaling 50 published cases. Overall, 67 % of cases demonstrated a response to temozolomide. Prolactin- and adrenocorticotrophic hormone (ACTH)-secreting tumors respond more frequently than non-functioning tumors. Response is typically evident in the first three months of treatment. Adverse effects occur in almost half of patients, although the majority are mild. The expression of a DNA repair enzyme, 06-methylguanine-DNA methyltransferase (MGMT), as determined by immunohistochemistry, appears to be the primary determinant of response to temozolomide in pituitary tumors. There is suggestion that MGMT may also play a role in pituitary tumorigenesis. Over the next few years we will see temozolomide used earlier in the treatment algorithm of aggressive pituitary tumors, making it imperative to collect global long-term data on its use.

Temozolomide in the Treatment of Aggressive Pituitary Tumours - An Overview of Existing Knowledge and Future Perspectives

2012 ◽  
Vol 7 (4) ◽  
pp. 228
Author(s):  
Ann McCormack ◽  
Keyword(s):  
Dna Methyltransferase ◽  
Treatment Algorithm ◽  
Pituitary Tumours ◽  
Methylguanine Dna Methyltransferase ◽  
Pituitary Tumorigenesis ◽  
Significant Efficacy ◽  
Primary Determinant ◽  
Acth Secreting ◽  
Term Data

The management of aggressive pituitary tumours remains a challenge, however, the recent identification of temozolomide as a chemotherapeutic agent with significant efficacy against these tumours has heralded a new therapeutic era. There has been an exponential growth in the international experience with temozolomide over the past five years, now totalling 50 published cases. Overall, 67 % of cases demonstrated a response to temozolomide. Prolactin- and adrenocorticotrophic hormone (ACTH)-secreting tumours respond more frequently than non-functioning tumours. Response is typically evident in the first three months of treatment. Adverse effects occur in almost half of patients, although the majority are mild. The expression of a DNA repair enzyme, 06-methylguanine-DNA methyltransferase (MGMT), as determined by immunohistochemistry, appears to be the primary determinant of response to temozolomide in pituitary tumours. There is suggestion that MGMT may also play a role in pituitary tumorigenesis. Over the next few years we will see temozolomide used earlier in the treatment algorithm of aggressive pituitary tumours, making it imperative to collect global long-term data on its use.

Temozolomide in the Treatment of Aggressive Pituitary Tumours – An Overview of Existing Knowledge and Future Perspectives

2010 ◽  
Vol 8 (2) ◽  
pp. 116
Author(s):  
Ann McCormack ◽  
Keyword(s):  
Dna Methyltransferase ◽  
Treatment Algorithm ◽  
Pituitary Tumours ◽  
Methylguanine Dna Methyltransferase ◽  
Pituitary Tumorigenesis ◽  
Significant Efficacy ◽  
Primary Determinant ◽  
Acth Secreting ◽  
Term Data

The management of aggressive pituitary tumours remains a challenge, however, the recent identification of temozolomide as a chemotherapeutic agent with significant efficacy against these tumours has heralded a new therapeutic era. There has been an exponential growth in the international experience with temozolomide over the past five years, now totalling 50 published cases. Overall, 67 % of cases demonstrated a response to temozolomide. Prolactin- and adrenocorticotrophic hormone (ACTH)-secreting tumours respond more frequently than non-functioning tumours. Response is typically evident in the first three months of treatment. Adverse effects occur in almost half of patients, although the majority are mild. The expression of a DNA repair enzyme, 06-methylguanine-DNA methyltransferase (MGMT), as determined by immunohistochemistry, appears to be the primary determinant of response to temozolomide in pituitary tumours. There is suggestion that MGMT may also play a role in pituitary tumorigenesis. Over the next few years we will see temozolomide used earlier in the treatment algorithm of aggressive pituitary tumours, making it imperative to collect global long-term data on its use.

scholarly journals Temozolomide Therapy for Aggressive Pituitary Tumors: Results in a Small Series of Patients from Argentina

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Oscar D. Bruno ◽  
Lea Juárez-Allen ◽  
Silvia B. Christiansen ◽  
Marcos Manavela ◽  
Karina Danilowicz ◽  
...  
Keyword(s):  
Pituitary Adenoma ◽  
Dna Methyltransferase ◽  
Pituitary Tumors ◽  
Cooperative Work ◽  
Minimum Time ◽  
Cushing's Disease ◽  
Nonfunctioning Pituitary Adenoma ◽  
Methylguanine Dna Methyltransferase ◽  
Small Series

We evaluated results of temozolomide (TMZ) therapy in six patients, aged 34–78 years, presenting aggressive pituitary tumors. In all the patients tested O6-methylguanine-DNA methyltransferase (MGMT) immunoexpression in surgical specimens was absent. Patients received temozolomide 140–320 mg/day for 5 days monthly for at least 3 months. In two patients minimum time for evaluation could not be reached because of death in a 76-year-old man with a malignant prolactinoma and of severe neutro-thrombopenia in a 47-year-old woman with nonfunctioning pituitary adenoma. In two patients (a 34-year-old acromegalic woman and a 39-year-old woman with Nelson’s syndrome) no response was observed after 4 and 6 months, respectively, and the treatment was stopped. Conversely, two 52- and 42-year-old women with Cushing’s disease had long-term total clinical and radiological remissions which persisted after stopping temozolomide. We conclude that TMZ therapy may be of variable efficacy depending on—until now—incompletely understood factors. Cooperative work on a greater number of cases of aggressive pituitary tumors should be crucial to establish the indications, doses, and duration of temozolomide administration.

scholarly journals Temozolomide Induces the Acquisition of Invasive Phenotype by O6-Methylguanine-DNA Methyltransferase (MGMT)+ Glioblastoma Cells in a Snail-1/Cx43-Dependent Manner

2021 ◽  
Vol 22 (8) ◽  
pp. 4150
Author(s):  
Paweł Kochanowski ◽  
Jessica Catapano ◽  
Maciej Pudełek ◽  
Tomasz Wróbel ◽  
Zbigniew Madeja ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Treatment Result ◽  
Dependent Manner ◽  
Down Regulation ◽  
Cx43 Expression ◽  
Cell Lineages ◽  
Methylguanine Dna Methyltransferase ◽  
U87 Cells ◽  
Invasive Cell

Glioblastoma multiforme (GBM) recurrences after temozolomide (TMZ) treatment result from the expansion of drug-resistant and potentially invasive GBM cells. This process is facilitated by O6-Methylguanine-DNA Methyltransferase (MGMT), which counteracts alkylating TMZ activity. We traced the expansion of invasive cell lineages under persistent chemotherapeutic stress in MGMTlow (U87) and MGMThigh (T98G) GBM populations to look into the mechanisms of TMZ-induced microevolution of GBM invasiveness. TMZ treatment induced short-term, pro-invasive phenotypic shifts of U87 cells, in the absence of Snail-1 activation. They were illustrated by a transient induction of their motility and followed by the hypertrophy and the signs of senescence in scarce U87 sub-populations that survived long-term TMZ stress. In turn, MGMThigh T98G cells reacted to the long-term TMZ treatment with the permanent induction of invasiveness. Ectopic Snail-1 down-regulation attenuated this effect, whereas its up-regulation augmented T98G invasiveness. MGMTlow and MGMThigh cells both reacted to the long-term TMZ stress with the induction of Cx43 expression. However, only in MGMThigh T98G populations, Cx43 was directly involved in the induction of invasiveness, as manifested by the induction of T98G invasiveness after ectopic Cx43 up-regulation and by the opposite effect after Cx43 down-regulation. Collectively, Snail-1/Cx43-dependent signaling participates in the long-term TMZ-induced microevolution of the invasive GBM front. High MGMT activity remains a prerequisite for this process, even though MGMT-related GBM chemoresistance is not necessary for its initiation.

Limiting numbers of G156A O6-methylguanine–DNA methyltransferase-transduced marrow progenitors repopulate nonmyeloablated mice after drug selection

Blood ◽  
2000 ◽  
Vol 95 (10) ◽  
pp. 3078-3084 ◽  
Author(s):  
Brian M. Davis ◽  
Omer N. Koç ◽  
Stanton L. Gerson
Keyword(s):  
Gene Therapy ◽  
Dna Methyltransferase ◽  
Drug Induced ◽  
Methylguanine Dna Methyltransferase ◽  
Patients With Cancer ◽  
Colony Forming Units ◽  
Dominant Selectable Marker ◽  
Selection For

Abstract The limited efficacy of hematopoietic gene therapy can be improved by in vivo selection for transduced long-term repopulating cells (LTRC). We selected for G156A MGMT (▵MGMT) transduced LTRC present in 5 × 104 to 100 × 104 marrow cells infused into nonmyeloablated mice by the administration of O6-benzylguanine (BG) and BCNU every 3 to 4 weeks. To facilitate engraftment, mice were given a nonablative dose of BG and BCNU before infusion. Without selection, ▵MGMT was not detected in any hematopoietic colony-forming units (CFU) 24 to 30 weeks after infusion. After BG and BCNU, ▵MGMT+ CFU were frequently detected, and their proportions increased with each treatment cycle. After 2 to 3 cycles of BG and BCNU, many mice were stably reconstituted with 75% to 100% ▵MGMT+ CFU for at least 6 months, representing up to 940-fold enrichment. Thus, BG and BCNU stem cell toxicity allows ▵MGMT-transduced LTRC to repopulate the bone marrow. This degree of selection pressure in nonmyeloablated mice is far greater than that observed in previous drug-resistance gene transfer studies. These data support our approved clinical trial to select for drug-resistant, transduced hematopoietic cells, potentially decreasing cumulative drug-induced myelosuppression in patients with cancer. These data also suggest that ▵MGMT may be a potent, dominant, selectable marker for use in dual gene therapy.

scholarly journals Differential Predictors and Clinical Implications Associated With Long-Term Survivors in IDH Wildtype and Mutant Glioblastoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Haihui Jiang ◽  
Kefu Yu ◽  
Yong Cui ◽  
Xiaohui Ren ◽  
Mingxiao Li ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Progression Free Survival ◽  
Clinical Implications ◽  
Therapeutic Implications ◽  
Methylguanine Dna Methyltransferase ◽  
Molecular Features ◽  
Younger Age ◽  
One Year ◽  
Long Term Survivors

BackgroundGlioblastoma (GBM) is the most aggressive intracranial tumor which can be divided into two subtypes based on status of isocitrate dehydrogenase (IDH). A small fraction of patients after receiving standard treatment can be long-term survivors (LTS). This study was designed to disclose the predictors and clinical implications associated with LTS in IDH wildtype and mutant GBM.MethodsPatients who survived beyond five years after diagnosis of GBM were defined as LTS, while those with a survival less than one year were defined as short-term survivors (STS). A total of 211 patients with diagnosis of GBM in Beijing Tiantan Hospital from January 2007 to January 2015 were enrolled, including 44 (20.9%) LTS and 167 (79.1%) STS. The clinical, radiological and molecular features between groups were systematically compared.ResultsCompared with STS, LTS were a subgroup of patients with a younger age at diagnosis (P=0.006), a higher KPS score (P=0.011), higher rates of cystic change (P=0.037), O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation (P=0.007), and IDH mutation (P=0.049), and more likely to have undergone gross total resection (P<0.001). Survival analysis demonstrated that LTS with wildtype IDH conferred a longer progression-free survival (66.0 vs. 27.0 months, P=0.04), but a shorter post-progression survival (46.5 months vs. not reached, P=0.0001) than those of LTS with mutant IDH. LTS with mutant IDH showed a trend towards increased survival after receiving re-operation (P=0.155) and reirradiation (P=0.127), while this clinical benefit disappeared in the subset of LTS with wildtype IDH (P>0.05).ConclusionThe prognostic value and therapeutic implications associated with LTS in GBM population significantly differed on the basis of IDH status. Our findings provide a new approach for physicians to better understand the two subtypes of GBM, which may assist in making more tailored treatment decisions for patients.

scholarly journals Long-Term Survival of Patients With Glioblastoma Treated With Radiotherapy and Lomustine Plus Temozolomide

2009 ◽  
Vol 27 (8) ◽  
pp. 1257-1261 ◽  
Author(s):  
Martin Glas ◽  
Caroline Happold ◽  
Johannes Rieger ◽  
Dorothee Wiewrodt ◽  
Oliver Bähr ◽  
...  
Keyword(s):  
Survival Data ◽  
Dna Methyltransferase ◽  
Standard Dose ◽  
Standard Group ◽  
Newly Diagnosed ◽  
Who Grade ◽  
Term Survival ◽  
Long Term Survival ◽  
Methylguanine Dna Methyltransferase

Purpose To evaluate long-term survival in a prospective series of patients newly diagnosed with glioblastoma and treated with a combination of lomustine (CCNU), temozolomide (TMZ), and radiotherapy. Patients and Methods Thirty-nine patients received radiotherapy of the tumor site only (60 Gy) and CCNU/TMZ chemotherapy (n = 31 received standard-dose CCNU, 100 mg/m2 on day 1 and TMZ 100 mg/m2/d on days 2 to 6; n = 8 received intensified-dose CCNU 110 mg/m2 on day 1 and TMZ 150 mg/m2 on days 2 to 6) for up to six courses. Results In the whole cohort, the median overall survival (mOS) was 23.1 months; 47.4% survived for 2 years, and 18.5% survived for 4 years. After a median follow-up of 41.5 months, mOS had not been reached in the intensified group and was significantly higher than in the standard group (22.6 months; P = .024). In the intensified group, four of eight patients survived for at least 56 months, two of them without recurrence. O6-methylguanine–DNA methyltransferase (MGMT) gene promotor methylation in the tumor tissue was associated with significantly longer mOS (methylated, 34.3 months v nonmethylated, 12.5 months). A multivariate Cox proportional hazard model revealed MGMT status (methylated v nonmethylated; relative risk [RR] of death, 0.43; P = .003) and chemotherapy dose (intensified v standard; RR, 0.37; P = .012) as independent prognostic factors. WHO grade 4 hematoxicity was observed more frequently in the intensified group (57% v 16%). Conclusion The combination of radiotherapy, CCNU, and TMZ yielded promising long-term survival data in patients with newly diagnosed glioblastoma. Intensification of CCNU/TMZ chemotherapy may add an additional survival benefit, albeit with greater acute toxicity.

scholarly journals Evaluation of prognostic utility of Ki-67, P53, and O-6-methylguanine-DNA methyltransferase expression in pituitary tumors

2019 ◽  
Vol 11 (04) ◽  
pp. 323-329 ◽  
Author(s):  
Chhanda Das ◽  
Pratap Mondal ◽  
Madhumita Mukhopadhyay ◽  
Satinath Mukhopadhyay ◽  
Ipsita Ghosh ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Pituitary Tumors ◽  
Response To Treatment ◽  
Ki 67 ◽  
Mgmt Expression ◽  
Methylguanine Dna Methyltransferase ◽  
Immunohistochemical Markers ◽  
Prognostic Utility ◽  
A Prospective Study ◽  
High Degree

Abstract BACKGROUND OR CONTEXT: Pituitary adenoma (PA) is the most common pathology of the pituitary gland. Pituitary tumors were historically considered benign, however, from recent advances in pathological and molecular analyses, numerous prognostic markers have been identified, allowing a better characterization of tumor behavior and prediction of response to treatment and recurrences. AIMS AND OBJECTIVES: Evaluation of the epidemiological occurrence of pituitary tumors in our center and prediction of the benign, aggressive, or malignant nature of the tumor with the help of immunohistochemical markers (IHC) Ki-67, P53, and O-6-methylguanine-DNA methyltransferase (MGMT) along with radiology. MATERIALS AND METHODS: A prospective study was done in 33 cases. Patients with clinically suspected pituitary tumors and related symptoms and signs are referred from the endocrine outpatient department and subsequently operated at the neurosurgery department were selected. We have studied the clinical features, radiology, histopathology, and IHC with the help of Ki-67, P53, and MGMT of PA over 2 years. RESULTS: We have 94% (31/33) cases of PA among them 94% (29/31) cases are macroadenoma. The IHC was conducted on 30 cases (excluding 1 case of pituitary apoplexy) where Ki-67, p53, and MGMT have been used for IHC in order to analyze the prognosis of the PA, irrespective of the immunological subtype of the PA. In our study, only 13% (4 patients) had MGMT score 0 and 2 patients, among these 4 patients having above cutoff level of Ki-67 and p53 value, considered as aggressive (in case of Ki-67 >3% and >50% in case of p53). When comparing MGMT expression with recurrence, a high degree of significance was found (Mann–Whitney U-test, P = 0.0038). Most of the recurrent tumors (6/9) had MGMT score 1 or below and most of the nonrecurring tumor had MGMT score 2 or above. When comparing MGMT expression with aggressiveness, a high degree of significance was found (Mann–Whitney U-test, P < 0.0001). Finally, combining the radiological Ki-67, p53, and MGMT values, two cases of aggressive adenoma have been seen in our study, the remaining being benign adenomas (WHO classification 2004). We did not encounter any case of pituitary carcinoma. MGMT did not show any significant correlation with radiological grading and histology. CONCLUSION: The benign, aggressive, or malignant nature of PA can be effectively predicted with the help of IHC, such as Ki-67, p53, and MGMT. This helps in better patient management and predicts recurrences and prognosis.

scholarly journals Pituitary tumors: genetic and molecular factors underlying pathogenesis and clinical behavior

2021 ◽  
Author(s):  
Anna Spada ◽  
Giovanna Mantovani ◽  
Donatella Treppiedi ◽  
Federica Mangili ◽  
Rosa Catalano ◽  
...  
Keyword(s):  
Clinical Phenotype ◽  
Pituitary Tumors ◽  
Clinical Behavior ◽  
Molecular Alterations ◽  
Behavior Understanding ◽  
Pituitary Tumorigenesis ◽  
Stimulatory G Protein ◽  
Specific Protease ◽  
Drug Responsiveness ◽  
Acth Secreting

Pituitary neuroendocrine tumors (PitNETs) are the most common intracranial neoplasms. Although generally benign, they can show a clinically aggressive course, with local invasion, recurrences and resistance to medical treatment. No universally accepted biomarkers of aggressiveness are available yet, and predicting clinical behavior of PitNETs remains a challenge. In rare cases the presence of germline mutations in specific genes predisposes to PitNETs formation, as part of syndromic diseases or familial isolated pituitary adenomas (FIPA), and associates to more aggressive, invasive and drug resistant tumors. The vast majority of cases is represented by sporadic PitNETs. Somatic mutations in the  subunit of stimulatory G protein gene (gsp) and in the ubiquitin-specific protease 8 (USP8) gene have been recognized as pathogenetic factors in sporadic GH- and ACTH-secreting PitNETs, respectively, without an association with a worse clinical phenotype. Other molecular factors have been found to significantly affect PitNETs drug responsiveness and invasive behavior. These molecules are cytoskeleton and/or scaffold proteins whose alterations prevent proper functioning of the somatostatin and dopamine receptors, targets of medical therapy, or promote the ability of tumor cells to invade surrounding tissues. The aim of the present review is to provide an overview of the genetic and molecular alterations that can contribute to determine PitNETs clinical behavior. Understanding subcellular mechanisms underlying pituitary tumorigenesis and PitNETs clinical phenotype will hopefully lead to identification of new potential therapeutic targets and new markers predicting the behavior and the response to therapeutic treatments of PitNETs.

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