Structure, Function, and Inhibition of O6-Alkylguanine-DNA Alkyltransferase

Ae, Pegg; Me, Dolan; Rc, Moschel

doi:10.1016/s0079-6603(08)60879-x

Cited by 466 publications

(453 citation statements)

References 171 publications

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“…groups are covalently linked to DNA bases. One way that cells repair this damage is by transferring the alkyl group off the DNA, a form of direct repair w x known as alkyltransfer repair 45,46 . Alkyltransfer repair has been found in bacteria, Archaea and euw x karyotes 47 .…”

Section: Alkylation Reõersalmentioning

confidence: 99%

A phylogenomic study of DNA repair genes, proteins, and processes

Eisen

Hanawalt

1999

Mutation Research/DNA Repair

418

334

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The ability to recognize and repair abnormal DNA structures is common to all forms of life. Studies in a variety of species have identified an incredible diversity of DNA repair pathways. Documenting and characterizing the similarities and differences in repair between species has important value for understanding the origin and evolution of repair pathways as Ž well as for improving our understanding of phenotypes affected by repair e.g., mutation rates, lifespan, tumorigenesis, . survival in extreme environments . Unfortunately, while repair processes have been studied in quite a few species, the ecological and evolutionary diversity of such studies has been limited. Complete genome sequences can provide potential sources of new information about repair in different species. In this paper, we present a global comparative analysis of DNA repair proteins and processes based upon the analysis of available complete genome sequences. We use a new form of analysis that combines genome sequence information and phylogenetic studies into a composite analysis we refer to as phylogenomics. We use this phylogenomic analysis to study the evolution of repair proteins and processes and to predict the repair phenotypes of those species for which we now know the complete genome sequence. q 1999 Elsevier Science B.V. All rights reserved.

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Section: Alkylation Reõersalmentioning

confidence: 99%

A phylogenomic study of DNA repair genes, proteins, and processes

Eisen

Hanawalt

1999

Mutation Research/DNA Repair

418

334

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“…These have been hampered by the similar toxicities of the two agents, and no useful increase in therapeutic index has been demonstrated (Micetich et al, 1992;Lee et al, 1993;Smith et al, 1996;Hammond et al, 2004). Because of this, interest has turned to inactivation of MGMT using inherently nontoxic pseudosubstrates for the protein, such as O 6 -benzylguanine (O 6 -BeG; reviewed in Pegg et al, 1995;Dolan and Pegg, 1997) and O 6 -(4-bromothenyl)guanine (PaTrin-2, Lomeguatrib;McElhinney et al, 1998;Middleton et al, 2002;Middleton and Margison, 2003).…”

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confidence: 99%

O6-(4-bromothenyl)guanine reverses temozolomide resistance in human breast tumour MCF-7 cells and xenografts

et al. 2005

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Tumour resistance to chemotherapy involving methylating agents such as DTIC (dacarbazine) and temozolomide is linked to expression of the DNA repair protein O 6 -alkylguanine-DNA alkyltransferase (MGMT). There is considerable interest in improving the efficacy of such O 6 -alkylating chemotherapy by the prior inactivation of MGMT. We have examined the effect of the modified guanine base, O 6 -(4-bromothenyl)guanine (PaTrin-2, Patrint, Lomeguatrib) on MGMT activity and cell or xenograft tumour growth inhibition by temozolomide in the human breast carcinosarcoma cell line, MCF-7. PaTrin-2 effectively inactivated MGMT in MCF-7 cells (IC 50 B6 nM) and in xenografts there was complete inactivation of MGMT within 2 h of dosing (20 mg kg À1 i.p.) and only slight recovery by 24 h. MGMT inactivation in a range of murine host tissues varied between complete and B60%, with extensive recovery by 24 h. PaTrin-2 (10 mM) substantially increased the growth inhibitory effects of temozolomide in MCF-7 cells (D 60 ¼ 10 mM with PaTrin-2 vs 400 mM without). In MCF-7 xenografts, neither temozolomide (100 mg kg À1 day À1 for 5 days) nor PaTrin-2 (20 mg kg À1 day À1 for 5 days) had any significant effect on tumour growth. In contrast, the PaTrin-2 -temozolomide combination produced a substantial tumour growth delay: median tumour quintupling time was increase by 22 days (Po0.005) without any significant increase in toxicity as assessed from animal weight. A PaTrin-2 -temozolomide combination may therefore be beneficial in the treatment of human breast cancers.

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“…1,2 MNNG and MNU produce O 6 -methylguanine, which mispairs with thymine during replication, resulting in conversion of a guanine-cytosine pair to an adenine-thymine pair if the adduct is not removed. 3,4 The O 6 -methylguanine-DNA methyltransferase, MGMT, is a DNA repair gene that removes mutagenic and cytotoxic adducts from the O 6 position of guanine induced by alkylating agents such as MNNG and MNU. 5 Therefore, inactivation of the MGMT gene can lead to G to A mutation.…”

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confidence: 99%

Promoter hypermethylation of MGMT is associated with protein loss in gastric carcinoma

et al. 2001

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Key words: DNA methylation, gastric carcinoma, MGMTN-methyl-NЈ-nitro-N-nitrosoguanidine (MNNG) and N-methyl-N-nitrosourea (MNU) have been shown to induce gastric carcinoma at a high frequency in rats and mice when given in their drinking water. 1,2 MNNG and MNU produce O 6 -methylguanine, which mispairs with thymine during replication, resulting in conversion of a guanine-cytosine pair to an adenine-thymine pair if the adduct is not removed. 3,4 The O 6 -methylguanine-DNA methyltransferase, MGMT, is a DNA repair gene that removes mutagenic and cytotoxic adducts from the O 6 position of guanine induced by alkylating agents such as MNNG and MNU. 5 Therefore, inactivation of the MGMT gene can lead to G to A mutation. In fact, MNU has been shown to induce tumors such as thymic lymphomas and lung adenomas MGMT knockout mice. 6 Epigenetic alterations, in addition to multiple genetic abnormalities, are deeply involved in the genesis and progression of human cancers. Methylation status of the CpG island in promoter regions is an important determinant of gene expression. Aberrant hypermethylation of the CpG island is associated with silencing of tumor suppressor genes in various tumors. Promoter hypermethylation and reduced MGMT expression has been found in some primary human carcinomas. [7][8][9] Data have also indicated that wild-type p53 may negatively regulate basal MGMT promoter activity. in vitro and in vivo studies have shown that induction of MGMT in the presence of DNAdamaging agents involves p53. 10,11 Transfection of MGMT promoter together with a p53-expression vector in both p53 knockout and p53 wild-type cells significantly reduced MGMT promoter activity. 10,12 No study, however, has been conducted to clarify the role and mechanism of MGMT alteration in gastric carcinoma.We examined DNA methylation of CpG islands of the MGMT gene by methylation specific PCR in 26 primary gastric carcinoma tissues and 8 gastric carcinoma cell lines and compared the results with levels of MGMT protein expression to know whether transcriptional silencing of MGMT occurs due to promoter hypermethylation. In addition, we investigated p53 mutation status in the same tissues by PCR-SSCP analysis for comparison with the levels of MGMT protein expression. MATERIAL AND METHODS Tissue samplesA total of 26 gastric carcinoma tissue samples from 26 cases were studied. Tumor tissues and their corresponding non-neoplastic mucosae were surgically removed, frozen immediately in liquid nitrogen, and stored at Ϫ80°C until use. We confirmed microscopically that the tumor-tissue specimens consisted mainly of carcinoma tissue and that non-neoplastic mucosa did not exhibit any tumor-cell invasion or show significant inflammatory involvement. Histologic classification and tumor staging were done according to Lauren classification system 13 and the TNM Stage Grouping. 14 Cell linesEight cell lines derived from human gastric carcinoma were used. The TMK-1 cell line was established in our laboratory from poorly-differentiated adenocarcinoma. 15 Five ga...

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Structure, Function, and Inhibition of O6-Alkylguanine-DNA Alkyltransferase

Cited by 466 publications

References 171 publications

A phylogenomic study of DNA repair genes, proteins, and processes

A phylogenomic study of DNA repair genes, proteins, and processes

O6-(4-bromothenyl)guanine reverses temozolomide resistance in human breast tumour MCF-7 cells and xenografts

Promoter hypermethylation of MGMT is associated with protein loss in gastric carcinoma

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