ABSTRACT
Malignant melanoma is an aggressive, highly lethal dermatological malignancy. Chemoresistance and rapid metastasis limit the curative effect of multimodal therapies like surgery or chemotherapy. The suicide enzyme O6-methylguanine-DNA methyltransferase (MGMT) removes adducts from the O6-position of guanine to repair DNA damage. High MGMT expression is associated with resistance to therapy in melanoma. However, it is unknown if MGMT is regulated by DNA methylation or histone acetylation in melanoma. We examined the effects of the DNA methylation inhibitor 5-Aza-2'-deoxycytidine and histone deacetylase inhibitor Trichostatin A alone or in combination on MGMT expression and promoter methylation and histone acetylation in A375, MV3, and M14 melanoma cells. This study demonstrates that MGMT expression, CpG island methylation, and histone acetylation vary between melanoma cell lines. Combined treatment with 5-Aza-2'-deoxycytidine and Trichostatin A led to reexpression of MGMT, indicating that DNA methylation and histone deacetylation are associated with silencing of MGMT in melanoma. This study provides information on the role of epigenetic modifications in malignant melanoma that may enable the development of new strategies for treating malignant melanoma.
Subject(s)
DNA Methylation/genetics , DNA Modification Methylases/biosynthesis , DNA Repair Enzymes/biosynthesis , Drug Resistance, Neoplasm/genetics , Gene Expression Regulation, Neoplastic/genetics , Histones/metabolism , Melanoma/genetics , Tumor Suppressor Proteins/biosynthesis , Acetylation , Antineoplastic Agents/pharmacology , Blotting, Western , Cell Line, Tumor , Chromatin Immunoprecipitation , Dacarbazine/analogs & derivatives , Dacarbazine/pharmacology , Humans , Reverse Transcriptase Polymerase Chain Reaction , Skin Neoplasms/genetics , TemozolomideABSTRACT
Penicillin is the gold standard for treating syphilis. However, allergic reactions, poor drug tolerance and limited efficacy in patients remain a challenging problem. The objective of this meta-analysis was to compare the efficacy of ceftriaxone and penicillin based on data obtained from published randomised controlled trials (RCTs). The Cochrane Library, Medline, EBSCO, EMBASE and Ovid databases were searched for RCTs of ceftriaxone vs. penicillin for the treatment of syphilis. Estimated risk ratios (RRs) and 95% confidence intervals (CIs) were used to investigate the following outcome measures: 3-month response rate; 6-month response rate; 12-month response rate; relapse rate; serofast rate; and failure rate. Seven RCTs involving 281 participants (159 patients who received ceftriaxone and 122 patients who received penicillin) were included in the meta-analysis. There were no significant differences in 3-month response rate (RR=1.12, 95% CI 0.89-1.42), 6-month response rate (RR=1.02, 95% CI 0.75-1.38), 12-month response rate (RR=1.04, 95% CI 0.82-1.32), relapse rate (RR=0.91, 95% CI 0.45-1.84), serofast rate (RR=0.69, 95% CI 0.22-2.12) or failure rate (RR=0.66, 95% CI 0.03-15.76) in patients treated with ceftriaxone compared with those treated with penicillin. In conclusion, there is no evidence in the literature that ceftriaxone is less efficient than penicillin.
