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, SR; Porteous, JK; Newlands, ES

doi:10.1038/bjc.1996.485

Cited by 106 publications

(66 citation statements)

References 54 publications

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“…Therefore, the sensitivity of tumour cells to TMZ is correlated with the activity of the DNA repair protein O 6 -alkylguanine alkyltransferase (AGT), which removes alkyl groups at the O 6 position of guanine. Cells with low levels of AGT are sensitive to TMZ, while cells expressing high levels of AGT are more resistant (Dolan et al, 1990;Wedge et al, 1996). O 6 -benzylguanine (O 6 -BG), a potent inhibitor of AGT-mediated resistant, enhances the activity of TMZ in tumour cells with high levels of AGT (Dolan et al, 1990;Wedge et al, 1996).…”

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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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confidence: 99%

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

et al. 2003

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“…High levels of this DNA repair protein have been shown in both cell culture and xenograft studies to produce resistance to temozolomide. AGT depletion by the substrate analogue O 6 -benzylguanine can resensitize tumor cells to temozolomide both in vitro (10,11) and in vivo (12).…”

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confidence: 99%

Poly(ADP-ribose) polymerase-1 inhibition reverses temozolomide resistance in a DNA mismatch repair–deficient malignant glioma xenograft

Cheng¹,

Johnson²,

Keir³

et al. 2005

Molecular Cancer Therapeutics

169

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Temozolomide is a DNA-methylating agent used in the treatment of malignant gliomas. In this study, we have examined if inhibition of poly(ADP-ribose) polymerase (PARP) could increase the cytotoxicity of temozolomide, particularly in cells deficient in DNA mismatch repair. Athymic mice, transplanted with mismatch repairproficient or deficient [D-245 MG (PR)] xenografts, were treated with a combination of temozolomide and the PARP inhibitor, INO-1001. For the tumors deficient in mismatch repair, the most effective dose of INO-1001 was found to be 150 mg/kg, given i.p. thrice at 4-hour intervals with the first injection in combination with 262.5 mg/kg temozolomide (0.75 LD 10 ). This dose of temozolomide by itself induced no partial regressions and a 4-day growth delay. In two separate experiments, the combination therapy increased the growth delay by 21.6 and 9.7 days with partial regressions observed in four of eight and three of nine mice, respectively. The addition of INO-1001 had a more modest, yet statistically significant, increase in tumor growth delay in the mismatch repair -proficient xenografts. In these experiments, mice were treated with a lower amount of temozolomide (88 mg/kg), which resulted in growth delays of 43.1 and 39.2 days. When the temozolomide treatment was in combination with 200 mg/kg INO-1001, there was an increase in growth delay to 48.9 and 45.7 days, respectively. These results suggest that inhibition of PARP may increase the efficacy of temozolomide in the treatment of malignant gliomas, particularly in tumors deficient in DNA mismatch repair. [Mol Cancer Ther 2005;4(9):1364-8]

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“…Temozolomide degrades spontaneously to MTIC at physiologic pH and, therefore, is not subject to high interpatient variability in its pharmacokinetics or tissue distribution (Figure 1). Temozolomide cytotoxicity appears to be mediated principally through methylation of DNA at the O 6 position of guanine (Catapano et al, 1987;D'Atri et al, 1995;Wedge et al, 1996), although other mechanisms have been proposed (Liu et al, 1997).…”

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confidence: 99%

“…Temozolomide has anti-tumour activity against a variety of human tumour xenografts and murine tumour models, including glioma, melanoma, mesothelioma, sarcoma and carcinomas of the colon and ovary (Stevens et al, 1987;Plowman et al, 1994;Carter et al, 1994;Friedman et al, 1995;Wedge et al, 1997a). Additionally, temozolomide has demonstrated additive or synergistic anti-tumour activity when administered in vitro with other chemotherapeutic agents, radiation and inhibitors of poly (ADP-ribose) polymerase and the DNA repair protein O 6 -alkylguanine-DNA alkyltransferase (OGAT) (Wedge et al, 1996(Wedge et al, , 1997bLiu et al, 1997). OGAT is responsible for removing DNA adducts from the O 6 position of guanine.…”

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confidence: 99%

Phase I dose-escalation and pharmacokinetic study of temozolomide (SCH 52365) for refractory or relapsing malignancies

et al. 1999

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Summary Temozolomide, an oral cytotoxic agent with approximately 100% bioavailability after one administration, has demonstrated schedule-dependent clinical activity against highly resistant cancers. Thirty patients with minimal prior chemotherapy were enrolled in this phase I trial to characterize the drug's safety, pharmacokinetics and anti-tumour activity, as well as to assess how food affects oral bioavailability. To determine dose-limiting toxicities (DLT) and the maximum tolerated dose (MTD), temozolomide 100-250 mg m -2 was administered once daily for 5 days every 28 days. The DLT was thrombocytopenia, and the MTD was 200 mg m -2 day -1 . Subsequently, patients received the MTD to study how food affects the oral bioavailability of temozolomide. When given orally once daily for 5 days, temozolomide was well tolerated and produced a non-cumulative, transient myelosuppression. The most common non-haematological toxicities were mild to moderate nausea and vomiting. Clinical activity was observed against several advanced cancers, including malignant glioma and metastatic melanoma. Temozolomide demonstrated linear and reproducible pharmacokinetics and was rapidly absorbed (mean T max~1 h) and eliminated (mean t 1/2 = 1.8 h). Food produced a slight reduction (9%) in absorption of temozolomide. Temozolomide 200 mg m -2 day -1 for 5 days, every 28 days, is recommended for phase II studies.

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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

Cited by 106 publications

References 54 publications

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

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

Poly(ADP-ribose) polymerase-1 inhibition reverses temozolomide resistance in a DNA mismatch repair–deficient malignant glioma xenograft

Phase I dose-escalation and pharmacokinetic study of temozolomide (SCH 52365) for refractory or relapsing malignancies

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