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.

Expression Silence of DNA Repair Gene hMGMT Induced by RNA Interference

Objective： MGMT protein expression has been associated with tumor resistance to alkylating agents. The objective of this paper is to construct the RNA interference vector which can specifically induce the expression silence of human DNA repair gene hMGMT. Methods： The hMGMT specific siRNA expression cassette was made by two steps PCR, linked with pUCI 9 to get pU6-MGMTi, co-transfected with pEGFP-CI into 16HBE and screened by G418. The MGMT mRNA and protein levels were detected by RT-PCR and Western Blot respectively. Results： hMGMT specific RNA interfere vector pU6-MGMTi was constructed successfully. In transfected 16HBE cells MGMT mRNA level could hardly be detected and the protein level was only 10% of control. Conclusion： MGMT specific RNAi expression cassette can effectively inhibit MGMT expression. MGMT silence cell line was built by co-transfection technology, which offered condition for studying the gene function of MGMT.

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.