Multicenter Phase II Trial of Temozolomide in Patients With Anaplastic Astrocytoma or Anaplastic Oligoastrocytoma at First Relapse

Yung, W.K. Alfred; Prados, Michael D.; Yaya-Tur, Ricardo; Rosenfeld, Steven S.; Brada, Michael; Friedman, Henry S.; Albright, Robert E.; Olson, Jeffrey J.; Chang, Susan M.; O’Neill, Ailbhe C.; Bruner, Janet M.; Yue, Nancy Chang; Dugan, Margaret; Zaknoen, Sara; Levin, Victor A.

doi:10.1200/jco.1999.17.9.2762

Cited by 700 publications

(436 citation statements)

References 33 publications

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“…TMZ has shown efficacy in primary brain tumours and metastatic melanoma in phase II trials (Bleehen et al, 1995;Yung et al, 1999) However, in a phase III trial, it was not found to be superior to DTIC (Middleton et al, 2000). In our study, an overall response rate of 31% (24 out of 74 patients) was achieved with a 1-year survival of 41% and a median survival of 252 days.…”

Section: Discussioncontrasting

confidence: 54%

Temozolomide followed by combined immunotherapy with GM-CSF, low-dose IL2 and IFNα in patients with metastatic melanoma

et al. 2003

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The purpose of this study is to determine the toxicity and efficacy of temozolomide (TMZ) p.o. followed by subcutaneous (s.c.) lowdose interleukin-2 (IL2), granulocyte -monocyte colony stimulating factor (GM-CSF) and interferon-a 2b (IFNa) in patients with metastatic melanoma. A total of 74 evaluable patients received, in four separate cohorts, escalating doses of TMZ (150 -250 mg m À2 ) for 5 days followed by s.c. IL2 (4 MIU m À2 ), GM-CSF (2.5 mg kg À1 ) and IFNa (5 MIU flat) for 12 days. A second identical treatment was scheduled on day 22 and cycles were repeated in stable or responding patients following evaluation. Data were analysed after a median follow-up of 20 months (12 -30 months). The overall objective response rate was 31% (23 out of 74; confidence limits 20.8 -42.9%) with 5% CR. Responses occurred in all disease sites including the central nervous system (CNS). Of the 36 patients with responding or stable disease, none developed CNS metastasis as the first or concurrent site of progressive disease. Median survival was 252 days (8.3 months), 1 year survival 41%. Thrombocytopenia was the primary toxicity of TMZ and was dose-and patientdependent. Lymphocytopenia (grade 3 -4 CTC) occurred in 48.5% (34 out of 70) fully monitored patients following TMZ and was present after immunotherapy in two patients. The main toxicity of combined immunotherapy was the flu-like syndrome (grade 3) and transient liver function disturbances (grade 2 in 20, grade 3 in 15 patients). TMZ p.o. followed by s.c. combined immunotherapy demonstrates efficacy in patients with stage IV melanoma and is associated with toxicity that is manageable on an outpatient basis.

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Section: Discussioncontrasting

confidence: 54%

Temozolomide followed by combined immunotherapy with GM-CSF, low-dose IL2 and IFNα in patients with metastatic melanoma

et al. 2003

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“…17 The cells treated with or without TMZ (100 mM) for 72 h were harvested by trypsinization, washed twice with PBS and fixed with ice-cold glutaraldehyde (3% in 0.1 M cacodylate buffer, pH 7.4) for 30 min. After washing in PBS the cells were postfixed in OsO 4 and embedded in Epon; 0.1 mm thin sections were stained with uranyl acetate/lead citrate (Fluka) and viewed in a Philips EM 400 electron microscope.…”

Section: Electron Microscopymentioning

confidence: 99%

“…3,4 TMZ has several advantages over other existing alkylating agents because of its unique characteristics. [5][6][7][8] Because TMZ is a small lipophilic molecule with a molecular weight of 194 Da, it can be administered orally and it crosses the blood-brain barrier effectively.…”

Section: Introductionmentioning

confidence: 99%

Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells

et al. 2004

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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 lM), TMZ induced autophagy, but not apoptosis in malignant glioma cells. After the treatment with TMZ, microtubule-associated protein lightchain 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 þ -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.

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“…Temozolomide (TMZ,3,-as-tetrazine-8-carboxamide) is a new oral alkylating agent that has recently demonstrated efficacy in the treatment of malignant gliomas (O'Reilly et al, 1993;Plowman et al, 1994;Friedman et al, 1995Friedman et al, , 2000Yung et al, 1999). The cytotoxicity of TMZ is primarily due to the formation of O 6 -methylguanine in DNA, which mispairs with thymine during the next cycle of DNA replication (Denny et al, 1994;D'Atri et al, 1995).…”

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confidence: 99%

Inhibition of telomerase activity in malignant glioma cells correlates with their sensitivity to temozolomide

et al. 2003

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Temozolomide (TMZ, 3,-as-tetrazine-8-carboxamide) is a new alkylating agent with promising antitumour efficacy for malignant gliomas. The resistance of tumour cells to TMZ is primarily associated with levels of the alkylguanine alkyltransferase (AGT). O 6 -benzylguanine (O 6 -BG), an inhibitor for AGT, reduced resistance to TMZ. Recently, it has been demonstrated that chemosensitivity of tumour cells is related to a decline in telomerase activity. However, it is unknown if TMZ sensitivity of malignant glioma cells correlates with telomerase. In this study, using malignant glioma cells with low levels of AGT (U373-MG and U87-MG) and high levels of AGT (T98G), we investigated the association among AGT, telomerase, and TMZ sensitivity. U373-MG and U87-MG cells were sensitive to TMZ (IC 50 for a 2-day treatment ¼ 100 mM), while T98G cells were resistant to TMZ (IC 50 for a 2-day treatment 4500 mM). Treatment with TMZ (100 mM) suppressed telomerase activity in U373-MG and U87-MG cells in a time-dependent manner, but not in T98G cells. The downregulation of telomerase activity in U373-MG and U87-MG cells was due to inhibition of the human telomerase reverse-transcriptase (hTERT) gene expression at the transcriptional level. This inhibitory effect was induced by interfering with transcription factor Sp1 binding sites of the hTERT core promoter. Interestingly, O 6 -BG not only sensitised T98G cells to TMZ, but also suppressed telomerase activity. These findings suggest that response of malignant glioma cells to TMZ can be monitored by reduction in telomerase activity. Therefore, quantification of telomerase activity during or after treatment with TMZ may be a useful marker to detect treatment efficacy.

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Multicenter Phase II Trial of Temozolomide in Patients With Anaplastic Astrocytoma or Anaplastic Oligoastrocytoma at First Relapse

Abstract: Temozolomide demonstrated good single-agent activity, an acceptable safety profile, and documented HQL benefits in patients with recurrent AA.

Cited by 700 publications

References 33 publications

Temozolomide followed by combined immunotherapy with GM-CSF, low-dose IL2 and IFNα in patients with metastatic melanoma

Temozolomide followed by combined immunotherapy with GM-CSF, low-dose IL2 and IFNα in patients with metastatic melanoma

Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells

Inhibition of telomerase activity in malignant glioma cells correlates with their sensitivity to temozolomide

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