O^6-methylguanine-DNA methyltransferase gene expression confers alkylation resistance to tumor cells

The emergence of drug resistance is a major obstacle limiting the successful chemotherapy of malignant tumors. Our previous studies have demonstrated that O^6-methylguanine-DNA methyltransferase (MGMT, EC 2.1.1.63) is an important contributor to tumor cellular resistance toward mono- and bifunctional alkylating agents, such as 1- (4-amino-2-methyl-5-pyrimidinyl) methyl-3- (2-chloroethyl) -3-nitrosourea (ACNU) and N-methyl-N’-nitro-N-nitrosoguanidine (MNNG). Mechanistically, MGMT can specifically remove the induced alkyl groups at the O^6-position of guanine which finally would lead to a G→ A transition or a lethal DNA interstrand cross-link unless repaired. Cells

Study on the Relationship Between Depletion of O^6-Methylguanine-DNA Methyltransferase and Cancer Chemotherapy

Drug resistance is still one of the major problems in cancer therapy. However, during the past several years, many efforts have been focused on reversing or depleting the molecular basis of drug resistance along with the elucidating of the mechanisms involved.Nitrosourea compounds such as 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) and 1, 3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) are an important class of useful antitumor drugs. They exert their antitumor activity by alkylating the O^6 position of guanine and leading to a DNA interstrand cross-link. Introcellular O^6-methylguanine-DNA methyltransferase (O^6-MT) can repair the mentioned DNA lesions and thus plays an important role in determining the sensitivity of

O^6-METHYLGUANINE-DNA METHYLTRANSFERASE AND HUMAN CANCER CHEMOTHERAPY

Two kinds of human tumor cell strains having different activity of O^6-methylguanine-DNA methyltransferase (O^6-MT) were transplanted into nude mice. Then the mice were inject-ed intraperitoneally with bifunctional alkylating agent 1--(4--amino--2-methyl--5--pyrimidinyl)methy1-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU). The tumors with low O^6-MTactivity were quickly suppressed or cured. The result suggests that some tumors, if previ-sionally determined with low O^6-MT activity, might be efficiently cured by treatment withACNU. This probably opens a new way for human cancer chemotherapy.

Promoter Hypermethylation of DNA Repair Gene MGMT in Laryngeal Squamous Cell Carcinoma

The relationship between hypermethylation of CpG islands in the promoter regions of O^6- methylguanine DNA methyhransferase （MGMT） genes and laryngeal squamous cell carcinoma was explored. Methylation-specific PCR and semi-quantitative RT-PCR were used to study the promoter methylation and mRNA expression of the MGMT gene in laryngeal carcinoma tissues, tissues adjacent to the tumor and normal laryngeal tissues. Hypermethylation of MGMT gene was detected in 16 samples of 46 （34.8 %） laryngeal squamous cell carcinoma samples. However, the MGMT hypermethylation was not detected in all tissues adjacent to the tumors and normal tissues. No significant difference in MGMT gene hypermethylation was found in samples with different histological grades （χ^2= 3. 130, P=0. 077） or in samples from patients with different TNM status （χ^2= 3. 957, P=0. 138）. No expression of MGMT mRNA was detected in all hypermethylated laryngeal carcinoma tissues. The expression of MGMT mRNA was detected in all unmethylated laryngeal carcinoma tissues, tissues adjacent to the tumors and normal tissues. It suggests that MGMT gene promoter hypermethylation is associated with MGMT gene transcription loss in laryngeal carcinoma tissues and possibly plays an important role in carcinogenesis of laryngeal tissues.

Molecular pathology and clinical implications of diffuse glioma

The prognosis for diffusely infiltrating gliomas at World Health Organization(WHO)grade 2-4 remains dismal due to their heterogeneity.The rapid development of genome-wide molecular-profiling-associated studies has greatly promoted the accuracy of glioma classification.Thus,the latest version of the WHO classification of the central nervous system tumors published in 2021 has incorporated more molecular biomarkers together with histological features for the diagnosis of gliomas.Advanced usage of molecular pathology in clinical diagnostic practice provides also new opportunities for the therapy of patients with glioma,including surgery,radiotherapy and chemotherapy,targeted therapy,immunotherapy,and more precision clinical trials.Herein,we highlight the updates in the classification of gliomas according to the latest WHO guidelines and summarize the clinically relevant molecular markers by focusing on their applications in clinical practice.We also review the advances in molecular features of gliomas,which can facilitate the development of glioma therapies,thereby discussing the challenges and future directions of molecular pathology toward precision medicine for patients with glioma.