Phase I trial of temozolomide (CCRG 81045: M&amp;B 39831: NSC 362856)

Newlands, E. S.; Blackledge, George; Slack, Joan; Rustin, G. J. S.; Smith, D. B.; Stuart, N. S. A.; Quarterman, Charmaine P.; Hoffman, Ronald; Stevens, M.F.G.; Brampton, M.

doi:10.1038/bjc.1992.57

Cited by 437 publications

(283 citation statements)

References 13 publications

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“…26,27 Orally administered, it readily crosses the blood-brain barrier. At physiologic pH, it undergoes rapid chemical conversion to methyl-triazeno-imidazole-carboxamide, the active drug.…”

Section: Temozolomidementioning

confidence: 99%

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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“…26,27 Orally administered, it readily crosses the blood-brain barrier. At physiologic pH, it undergoes rapid chemical conversion to methyl-triazeno-imidazole-carboxamide, the active drug.…”

Section: Temozolomidementioning

confidence: 99%

Treatment of pituitary neoplasms with temozolomide

Syro

Ortíz

Scheithauer

et al. 2010

Cancer

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“…Temozolomide is well tolerated (Newlands et al, 1992;O'Reilly et al, 1993;Bleehen et al, 1995;Dhodapkar et al, 1997), with thrombocytopaenia as the main toxicity. This is usually self-limiting and most patients recover by day 28.…”

mentioning

confidence: 99%

Phase I study of temozolomide plus paclitaxel in patients with advanced malignant melanoma and associated in vitro investigations

et al. 2005

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The purpose of this study was to determine activity of temozolomide combined with paclitaxel or epothilone B in vitro, and to investigate the combination of temozolomide with paclitaxel in a Phase I clinical trial. Melanoma cell lines A375P and DX3 were treated with temozolomide and either paclitaxel or epothilone B. Combination indices were determined to assess the degree of synergism. In a clinical study, 21 patients with malignant melanoma were treated with increasing doses of temozolomide (orally, days 1 -5), in combination with a fixed dose of paclitaxel (i.v. infusion day 1), followed by dose escalation of the latter drug. Cycles of treatment were repeated every 3 weeks. Pharmacokinetics of both agents were determined on day 1, with temozolomide pharmacokinetics also assessed on day 5. All three compounds were active against the melanoma cell lines, with epothilone B being the most potent. There was a strong degree of synergism between temozolomide and either paclitaxel or epothilone B. In the clinical study, no pharmacokinetic interaction was observed between temozolomide and paclitaxel. Dose escalation of both drugs to clinically active doses was possible, with no dose-limiting toxicities observed at 200 mg m À2 day À1 temozolomide and 225 mg m À2 day À1 paclitaxel. There were two partial responses out of 15 evaluable patients. One patient remains alive and symptom-free at 4 years after treatment. Temozolomide and paclitaxel may be administered safely at clinically effective doses. Further evaluation of these combinations in melanoma is warranted.

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“…Temozolomide has recently demonstrated promising clinical activity in the treatment of glioblastoma and melanoma (Newlands et al, 1992;O'Reilly et al, 1993), while BCNU is an established agent for the treatment of many malignancies, including glioma and lymphoma (Young et al, 1971;Edwards et al, 1980). Nevertheless, the activity of DNA-alkylating chemotherapy is frequently compromised by the development of resistance; a phenomenon often related to the DNA repair capacity of the tumour cell (Harris et al, 1983;Ludlum, 1990).…”

mentioning

confidence: 99%

3-aminobenzamide and/or O6-benzylguanine evaluated as an adjuvant to temozolomide or BCNU treatment in cell lines of variable mismatch repair status and O6-alkylguanine-DNA alkyltransferase activity

Wedge

Porteous²,

Newlands³

1996

Br J Cancer

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106

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Summary 06-benzylguanine (06-BG) and 3-aminobenzamide (3-AB) inhibit the DNA repair proteins o6_ alkylguanine-DNA alkyltransferase (AGT) and poly(ADP-ribose) polymerase (PARP) respectively. The effect of 06-BG and/or 3-AB on temozolomide and 1,3-bis(2-chloroethyl)-nitrosourea (BCNU) cytotoxicity, was assessed in seven human tumour cell lines: six with an AGT activity of >80 fmol mg-' protein (Mer+) and one with an AGT activity of <3 fmol mg protein (Mer-). Three of the Mer+ cell lines (LS174T, DLD1 and HCT1 16) were considered to exhibit resistance to methylation by a mismatch repair deficiency (MMR-), each being known to exhibit microsatellite instability, and DLD1 and HCT1 16 having well-characterised defects in DNA mismatch binding. Potentiation was defined as the ratio between an IC50 achieved without and with a particular inhibitor treatment. Temozolomide or BCNU cytotoxicity was not potentiated by either inhibitor in the Mer-cell line. Preincubation with 06-BG (100 /M for 1 h) was found to potentiate the cytotoxicity of temozolomide by 1.35-to 1.57-fold in Mer+/MMR+ cells, but had no significant effect in Mer+/MMR-cells.In comparison, 06-BG pretreatment enhanced BCNU cytotoxicity by 1.94-to 2.57-fold in all Mer+ cell lines. Post-incubation with 3-AB (2 mm, 48 h) potentiated temozolomide by 1.35-to 1.59-fold in Mer+/MMR+ cells, and when combined with 06-BG pretreatment produced an effect which was at least additive, enhancing cytotoxicity by 1.97-to 2.16-fold. 3-AB treatment also produced marked potentiation (2.20-to 3.12-fold) of temozolomide cytotoxicity in Mer+/MMR-cells. In contrast, 3-AB produced marginal potentiation of BCNU cytotoxicity in only three cell lines (1.19-to 1.35-fold), and did not enhance the cytotoxicity of BCNU with o6_ BG treatment in any cell line. These data suggest that the combination of an AGT and PARP inhibitor may have a therapeutic role in potentiating temozolomide activity, but that the inhibition of poly(ADP-ribosyl)ation has little effect on the cytotoxicity of BCNU.

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Phase I trial of temozolomide (CCRG 81045: M&B 39831: NSC 362856)

Cited by 437 publications

References 13 publications

Treatment of pituitary neoplasms with temozolomide

Treatment of pituitary neoplasms with temozolomide

Phase I study of temozolomide plus paclitaxel in patients with advanced malignant melanoma and associated in vitro investigations

3-aminobenzamide and/or O6-benzylguanine evaluated as an adjuvant to temozolomide or BCNU treatment in cell lines of variable mismatch repair status and O6-alkylguanine-DNA alkyltransferase activity

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