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.

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.

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.

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 Temozolomide treatment of a pituitary carcinoma and two pituitary macroadenomas resistant to conventional therapy

2009 ◽  
Vol 161 (4) ◽  
pp. 631-637 ◽  
Author(s):  
C Hagen ◽  
H D Schroeder ◽  
S Hansen ◽  
C Hagen ◽  
M Andersen
Keyword(s):  
Dna Methyltransferase ◽  
English Literature ◽  
Tumour Size ◽  
Tumour Volume ◽  
Pituitary Tumour ◽  
Tumour Mass ◽  
Pituitary Tumours ◽  
Hormone Levels ◽  
Mass Effects ◽  
Methylguanine Dna Methyltransferase

ObjectiveAggressive pituitary tumours may be difficult to treat. Temozolomide (TMZ) is an alkylating cytostaticum. In a small number of cases, TMZ therapy has been reported to reduce pituitary tumour size and hormone hypersecretion.DesignWe present three patients with pituitary tumours treated with TMZ. One tumour was initially a macroprolactinoma that developed into a mixed GH- and prolactin-secreting carcinoma (patient A). To our knowledge, this is the first published in English literature. Two adenomas, a macroprolactinoma (patient B) and a clinically non-functioning pituitary adenoma (patient C), were highly invasive. The three patients suffered from extensive tumour mass effects, and all tumours were resistant to conventional treatment.MethodTMZ, 150–200 mg/m2 of body surface area was administered orally for 5 days during each 28-day cycle.ResultDuring TMZ therapy, tumour sizes were significantly reduced, hormone levels normalized and symptoms of mass effects decreased in all three cases. The carcinoma was treated from 2004 to 2006 (23 months). Three years after the terminating treatment, the tumour has not regrown and hormone levels are normalized. Immunohistochemical staining for methylguanine DNA methyltransferase (MGMT) was negative in two patients (A and B), and in one patient (C) a few nuclei stained positive.ConclusionTMZ therapy significantly decreased tumour volume, hormone hypersecretion and symptoms in all three patients, corresponding to the pathological findings regarding MGMT. TMZ therapy may be a new option for the treatment of resistant pituitary adenomas.

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.

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