Clinical Relevance of MGMT in the Treatment of Cancer

Abstract

Anumber of DNA-damaging chemotherapeutic agents attack the O(6) position on guanine, forming the most potent cytotoxic DNA adducts known. The DNA repair enzyme O(6)-alkylguanine DNA alkyltransferase (AGT), encoded by the gene MGMT, repairs alkylation at this site and is responsible for protecting both tumor and normal cells from these agents. Cells and tissues vary greatly in AGT expression, not only between tissues but also between individuals. AGT activity correlates inversely with sensitivity to agents that form O(6)-alkylguanine DNA adducts, such as carmustine (BCNU), temozolomide, streptozotocin, and dacarbazine. The one exception is those tumors lacking mismatch repair, which renders them resistant to methylating agents. A recent study in patients with gliomas confirmed the correlation between low-level expression of the MGMT gene and response and survival after BCNU. An inhibitor to AGT, O(6)-benzylguanine (BG), depletes AGT in human tumors without associated toxicity and is now in phase II clinical trials. Finally, mutations within the active site region of the MGMT gene render the AGT protein resistant to BG inactivation. As a result, mutant MGMT gene transfer into hematopoietic stem cells has been shown to selectively protect the marrow from the combination of an alkylating agent and BG, while at the same time sensitizing tumor cells. MGMT remains a paradigm for development of new agents that modulate known mechanisms of drug resistance in cancer cells and raise the spectra of combinatorial therapies that encompass known drug resistance mechanisms.

Dynamics of chemosensitivity and chromosomal instability in recurrent glioblastoma

“…With respect to temozolomide response, expression of the repair enzyme MGMT was suggested as the major resistance factor (Gerson, 2002) and lack of MGMT expression in gliomas is mainly based on gene promoter methylation (Silber et al, 1998;Esteller et al, 1999Esteller et al, , 2000. Recently, promoter methylation was shown to represent an independent prognostic factor in glioblastoma patients (Hegi et al, 2005) and to be associated with enhanced overall survival after treatment with RT/temozolomide (Hegi et al, 2004).…”

Treatment of pituitary neoplasms with temozolomide

“…36 It plays the role of removing alkylating adducts induced by temozolomide treatment, thereby counteracting its antineoplastic action. 37,38 It appears that high tumor expression of MGMT confers resistance to temozolomide. It is widely believed that low-level expression in a wide spectrum of human tumors results from epigenetic silencing of the MGMT gene, largely because of hypermethylation of its promoter.…”

“…During tumorigenesis, loss of MGMT expression and impaired capability of DNA repair have been observed. 37,38,41 In contrast, MGMT overexpression has prevented carcinogenesis in mouse models. 37 In low-grade astrocytomas, lack of MGMT expression has been considered a marker of malignant transformation.…”

“…37,38,41 In contrast, MGMT overexpression has prevented carcinogenesis in mouse models. 37 In low-grade astrocytomas, lack of MGMT expression has been considered a marker of malignant transformation. 54 The issue of promoter methylation of the MGMT gene is important for diminished MGMT function.…”

Dose finding and O6-alkylguanine-DNA alkyltransferase study of cisplatin combined with temozolomide in paediatric solid malignancies

“…The cytotoxicity and antitumour activity of temozolomide is determined largely by methylation of DNA at the O 6 -position of guanine and the mismatch repair system, and is inversely related to the activity of the DNA repair protein O 6 -Alkyguanine-DNA alkyltransferase (also known as O 6 -methylguanine-DNA methyltransferase (MGMT)) (Karran and Hampson, 1996;Pegg, 2000;Gerson, 2002;Tentori and Graziani, 2002). Modulation of MGMT activity using pseudosubstrate inhibitors such as O 6 -benzylguanine (O 6 BG) (Dolan et al, 1994) and more recently O 6 -(4-bromothenyl)guanine (PaTrin-2) (Middleton et al, 2000a) results in depletion of MGMT and increased sensitivity to DNA alkylating or crosslinking agents, including temozolomide, carmustine, lomustine (Dolan et al, 1990;Plowman et al, 1994;Liu et al, 1996;Wedge et al, 1996) and cisplatin Fishel et al, 2003).…”