Temozolomide

Temozolomide, an alkylating agent, is a DNA damage inducer.

Is more better? The impact of extended adjuvant temozolomide in newly diagnosed glioblastoma: a secondary analysis of EORTC and NRG Oncology/RTOG.[Pubmed:28371907]

Neuro Oncol. 2017 Aug 1;19(8):1119-1126.

Background: Radiation with concurrent and adjuvant (6 cycles) Temozolomide (TMZ) is the established standard of postsurgical care for newly diagnosed glioblastoma (GBM). This regimen has been adopted with variations, including extending TMZ beyond 6 cycles. The optimal duration of maintenance therapy remains controversial. Methods: We performed pooled analysis of individual patient data from 4 randomized trials for newly diagnosed GBM. All patients who were progression free 28 days after cycle 6 were included. The decision to continue TMZ was per local practice and standards, and at the discretion of the treating physician. Patients were grouped into those treated with 6 cycles and those who continued beyond 6 cycles. Progression-free and overall survival were compared, adjusted by age, performance status, resection extent, and MGMT methylation. Results: A total of 2214 GBM patients were included in the 4 trials. Of these, 624 qualified for analysis 291 continued maintenance TMZ until progression or up to 12 cycles, while 333 discontinued TMZ after 6 cycles. Adjusted for prognostic factors, treatment with more than 6 cycles of TMZ was associated with a somewhat improved progression-free survival (hazard ratio [HR] 0.80 [0.65-0.98], P = .03), in particular for patients with methylated MGMT (n = 342, HR 0.65 [0.50-0.85], P < .01). However, overall survival was not affected by the number of TMZ cycles (HR = 0.92 [0.71-1.19], P = .52), including the MGMT methylated subgroup (HR = 0.89 [0.63-1.26], P = .51). Conclusions: Continuing TMZ beyond 6 cycles was not shown to increase overall survival for newly diagnosed GBM.

Prolonged Temozolomide Maintenance Therapy in Newly Diagnosed Glioblastoma.[Pubmed:28360216]

Oncologist. 2017 May;22(5):570-575.

BACKGROUND: The impact of prolonging Temozolomide (TMZ) maintenance beyond six cycles in newly diagnosed glioblastoma (GBM) remains a topic of discussion. We investigated the effects of prolonged TMZ maintenance on progression-free survival (PFS) and overall survival (OS). PATIENTS AND METHODS: In this retrospective single-center cohort study, we included patients with GBM who were treated with radiation therapy with concomitant and adjuvant TMZ. For analysis, patients were considered who either completed six TMZ maintenance cycles (group B), continued with TMZ therapy beyond six cycles (group C), or stopped TMZ maintenance therapy within the first six cycles (group A). Patients with progression during the first six TMZ maintenance cycles were excluded. RESULTS: Clinical data from 107 patients were included for Kaplan-Meier analyses and 102 for Cox regressions. Median PFS times were 8.1 months (95% confidence interval [CI] 6.1-12.4) in group A, 13.7 months (95% CI 10.6-17.5) in group B, and 20.9 months (95% CI 15.2-43.5) in group C. At first progression, response rates of TMZ/lomustine rechallenge were 47% in group B and 13% in group C. Median OS times were 12.7 months (95% CI 10.3-16.8) in group A, 25.2 months (95% CI 17.7-55.5) in group B, and 28.6 months (95% CI 24.4-open) in group C. Nevertheless, multivariate Cox regression for patients in group C compared with group B that accounted for imbalances of other risk factors showed no different relative risk (RR) for OS (RR 0.77, p = .46). CONCLUSION: Our data do not support a general extension of TMZ maintenance therapy beyond six cycles. The Oncologist 2017;22:570-575 IMPLICATIONS FOR PRACTICE: Radiation therapy with concomitant and adjuvant Temozolomide (TMZ) maintenance therapy is still the standard of care in patients below the age of 65 years in newly diagnosed glioblastoma. However, in clinical practice, many centers continue TMZ maintenance therapy beyond six cycles. The impact of this continuation is controversial and has not yet been addressed in prospective randomized clinical trials. We compared the effect of more than six cycles of TMZ in comparison with exactly six cycles on overall survival (OS) and progression-free survival (PFS) by multivariate analysis and found a benefit in PFS but not OS. Thus, our data do not suggest prolonging TMZ maintenance therapy beyond six cycles, which should be considered in neurooncological practice.

Lithium enhances the antitumour effect of temozolomide against TP53 wild-type glioblastoma cells via NFAT1/FasL signalling.[Pubmed:28359080]

Br J Cancer. 2017 May 9;116(10):1302-1311.

BACKGROUND: We previously showed that activation of the nuclear factor of activated T cells (NFAT)1/Fas ligand (FasL) pathway induces glioma cell death. Lithium (Li) is an inhibitor of glycogen synthase kinase (GSK)-3 that activates NFAT1/FasL signalling. Temozolomide (TMZ) inhibits GSK-3 and activates Fas in tumour protein (TP)53 wild-type (TP53wt) glioma cells. The present study investigated the combinational effects of TMZ and low-dose Li on TP53wt glioma cells. METHODS: The combined effect of TMZ and Li was examined in TP53wt U87 and primary glioma cells and a mouse xenograft model. RESULTS: Combination with 1.2 mM Li potentiated TMZ-induced cell death in TP53wt glioma cells, as determined by neurosphere formation and apoptosis assays. Temozolomide combined with Li treatment inhibited GSK-3 activation, promoted NFAT1 nuclear translocation and upregulated Fas/FasL expression. Targeted knockdown of NFAT1 expression blocked the induction of cell death by TMZ and Li via FasL inhibition. In vivo, combined treatment with TMZ and Li suppressed tumour growth and prolonged the survival of tumour-bearing mice. However, the combination of TMZ and Li did not produce a statistically significant effect in TP53mut glioma cells. CONCLUSIONS: Temozolomide combined with low-dose Li induces TP53wt glioma cell death via NFAT1/FasL signalling. This represents a potential therapeutic strategy for TP53wt glioma treatment.

Timed sequential therapy of the selective T-type calcium channel blocker mibefradil and temozolomide in patients with recurrent high-grade gliomas.[Pubmed:28371832]

Neuro Oncol. 2017 Jun 1;19(6):845-852.

Background: Mibefradil (MIB), previously approved for treatment of hypertension, is a selective T-type calcium channel blocker with preclinical activity in high-grade gliomas (HGGs). To exploit its presumed mechanism of impacting cell cycle activity (G1 arrest), we designed a phase I study to determine safety and the maximum tolerated dose (MTD) of MIB when given sequentially with Temozolomide (TMZ) in recurrent (r)HGG. Methods: Adult patients with rHGG >/=3 months from TMZ for initial therapy received MIB in 4 daily doses (q.i.d.) for 7 days followed by standard TMZ at 150-200 mg/m2 for 5 days per 28-day cycle. MIB dose escalation followed a modified 3 + 3 design, with an extension cohort of 10 patients at MTD who underwent 3'-deoxy-3'-18F-fluorothymidine (18F-FLT) PET imaging, to image proliferation before and after 7 days of MIB. Results: Twenty-seven patients were enrolled (20 World Health Organization grade IV, 7 grade III; median age 50 y; median KPS 90). The MTD of MIB was 87.5 mg p.o. q.i.d. Dose-limiting toxicities were elevation of alanine aminotransferase/aspartate aminotransferase (grade 3) and sinus bradycardia. The steady-state maximum plasma concentration of MIB at the MTD was 1693 +/- 287 ng/mL (mean +/- SD). 18F-FLT PET imaging showed a significant decline in standardized uptake value (SUV) signal in 2 of 10 patients after 7 days of treatment with MIB. Conclusions: MIB followed by TMZ was well tolerated in rHGG patients at the MTD. The lack of toxicity and presence of some responses in this selected patient population suggest that this regimen warrants further investigation.

Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells.[Pubmed:14713959]

Cell Death Differ. 2004 Apr;11(4):448-57.

Autophagy is originally named as a process of protein recycling. It begins with sequestering cytoplasmic organelles in a membrane vacuole called autophagosome. Autophagosomes then fuse with lysosomes, where the materials inside are degraded and recycled. To date, however, little is known about the role of autophagy in cancer therapy. In this study, we present that Temozolomide (TMZ), a new alkylating agent, inhibited the viability of malignant glioma cells in a dose-dependent manner and induced G2/M arrest. At a clinically achievable dose (100 microM), TMZ induced autophagy, but not apoptosis in malignant glioma cells. After the treatment with TMZ, microtubule-associated protein light-chain 3 (LC3), a mammalian homologue of Apg8p/Aut7p essential for amino-acid starvation-induced autophagy in yeast, was recruited on autophagosome membranes. When autophagy was prevented at an early stage by 3-methyladenine, a phosphatidylinositol 3-phosphate kinase inhibitor, not only the characteristic pattern of LC3 localization, but also the antitumor effect of TMZ was suppressed. On the other hand, bafilomycin A1, a specific inhibitor of vacuolar type H(+)-ATPase, that prevents autophagy at a late stage by inhibiting fusion between autophagosomes and lysosomes, sensitized tumor cells to TMZ by inducing apoptosis through activation of caspase-3 with mitochondrial and lysosomal membrane permeabilization, while LC3 localization pattern stayed the same. These results indicate that TMZ induces autophagy in malignant glioma cells. Application of an autophagy inhibitor that works after the association of LC3 with autophagosome membrane, such as bafilomycin A1, is expected to enhance the cytotoxicity of TMZ for malignant gliomas.

Antitumor imidazotetrazines. 32. Synthesis of novel imidazotetrazinones and related bicyclic heterocycles to probe the mode of action of the antitumor drug temozolomide.[Pubmed:7739008]

J Med Chem. 1995 Apr 28;38(9):1493-504.

A series of new imidazo[5,1-d]-1,2,3,5-tetrazinones with additional hydrogen-bonding or ionic substituents at the 8-carboxamide position of the antitumor drugs Temozolomide (1) and mitozolomide (2) has been prepared. None of these compounds were significantly more cytotoxic in vitro against the mouse TLX5 lymphoma than the lead structures. Molecular modeling techniques have been used to design benzo- and pyrazolo[4,3-d]-1,2,3-triazinones bearing carboxamide groups in appropriate positions which are isosteric with Temozolomide and mitozolamide but which cannot ring open to alkylating species. As predicted, these compounds have no inhibitory properties against human GM892A or Raji cell lines in vitro. Temozolomide and the spermidine-Temozolomide conjugate 28 preferentially methylate guanines within guanine-rich sequences in DNA, but no experimental evidence has been found to support the hypothesis that such regions are involved in catalyzing the ring opening of the imidazotetrazinone prodrugs to their active forms.

Preclinical antitumor activity of temozolomide in mice: efficacy against human brain tumor xenografts and synergism with 1,3-bis(2-chloroethyl)-1-nitrosourea.[Pubmed:8033099]

Cancer Res. 1994 Jul 15;54(14):3793-9.

Temozolomide, a methylating agent with clinical activity against brain tumors, demonstrated excellent antitumor activity following p.o. administration to athymic mice bearing human brain tumor xenografts. In the early stage s.c. implanted SNB-75 astrocytoma model, a 400-mg/kg dose administered on Day 5 produced 10 of 10 Day 54 tumor-free mice. In later staged s.c. U251 and SF-295 glioblastoma models, a single 600-mg/kg dose produced 9 of 10 Day 86 and 2 of 10 Day 40 tumor-free mice, respectively. In the latter group, a tumor growth delay of > 315% was attained. Similar levels of activity were attained with equal total doses on schedules of daily for 5 doses and every fourth day for 3 doses. A single 40-mg/kg i.v. dose of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) also demonstrated excellent activity, producing 9 of 10 tumor-free mice in the SNB-75 model and growth delays of 283 and 301% in the U251 and SF-295 models, respectively. Temozolomide was also highly effective against intracerebral implants of the U251 and SF-295 glioblastomas. Administration of either 600 mg/kg on Day 1 or 200 mg/kg on Days 1, 5, and 9 produced 7 of 9 Day 90 tumor-free mice in the U251 model. In the SF-295 model, a single 400-mg/kg dose or three 200-mg/kg doses produced 3 and 4 of 10 Day 90 tumor-free mice, respectively, and prolonged survival by 127%. A single 40-mg/kg i.v. dose of BCNU was more effective than Temozolomide in the intracerebral SF-295 model, and less effective in the intracerebral U251 model. The synergistic potential of Temozolomide and BCNU in combination was evaluated in an advanced stage s.c. implanted SF-295 model. When Temozolomide was administered 2 h after BCNU on a single treatment day, a dramatic synergistic therapeutic effect was observed in two experiments. For example, single agent doses of Temozolomide (600 mg/kg) and BCNU (60 mg/kg) and a combination (400 mg/kg + 27 mg/kg) demonstrating equivalent toxicity produced growth delays of 190, 258, and > 492% (includes 5 of 10 Day 51 tumor-free mice), respectively. Analysis of the data by a quadratic dose response model indicated synergism with significance at P = 0.0001 in both experiments. Synergism also was demonstrated by the isobole method. The reverse sequence was more toxic, but at lower combination doses a synergistic effect was still observed (P = 0.0001).(ABSTRACT TRUNCATED AT 400 WORDS)

Temozolomide (NSC 362856) is an oral active DNA alkylating agent that crosses the blood-brain barrier. Temozolomide is also a proautophagic and proapoptotic agent. Temozolomide is effective against tumor cells that are characterized by low levels of O6-alkylguanine DNA alkyltransferase (OGAT) and a functional mismatch repair system. Temozolomide has antitumor and antiangiogenic effects.

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