It has been suggested that cancer represents an alteration in DNA, heritable by progeny cells, that leads to abnormally regulated expression of normal cellular genes; DNA alterations such as mutations, rearrangements and changes in methylation have been proposed to have such a role. Because of increasing evidence that DNA methylation is important in gene expression (for review see refs 7, 9-11), several investigators have studied DNA methylation in animal tumours, transformed cells and leukaemia cells in culture. The results of these studies have varied; depending on the techniques and systems used, an increase, decrease, or no change in the degree of methylation has been reported. To our knowledge, however, primary human tumour tissues have not been used in such studies. We have now examined DNA methylation in human cancer with three considerations in mind: (1) the methylation pattern of specific genes, rather than total levels of methylation, was determined; (2) human cancers and adjacent analogous normal tissues, unconditioned by culture media, were analysed; and (3) the cancers were taken from patients who had received neither radiation nor chemotherapy. In four of five patients studied, representing two histological types of cancer, substantial hypomethylation was found in genes of cancer cells compared with their normal counterparts. This hypomethylation was progressive in a metastasis from one of the patients.

Hypomethylation distinguishes genes of some human cancers from their normal counterparts.

Isolation and synthesis of biologically active carbazole alkaloids

Cyclizations of N-acyliminium ions.

Intramolecular reactions of N-acyliminium intermediates

Publisher Summary This chapter focuses on 5-methylcytosine, gene regulation, and cancer. The regulation of mammalian gene expression clearly is accomplished by multiple control systems operating at several levels. Some obvious levels of control include chromosome condensation, chromatin structure transcriptional control by repressors and activators, RNA processing, and translational control. The chapter presents the argument for a newly recognized additional component of mammalian gene control and enzymatic DNA methylation and points out the relevance of this gene control system to cancer. Mammalian DNA is modified shortly after replication by the enzymatic conversion of about 3% of cytosines to 5-methylcytosine. 5-Methylcytosine is the only naturally occurring modified base yet found in mammalian DNA. The chapter focuses primarily on the work of the past 2 years, considering first the general aspects of methylation and gene control and then the cancer-related aspects.

5-Methylcytosine, Gene Regulation, and Cancer

A stereospecific route to aziridinomitosanes: the synthesis of novel mitomycin congeners

Stereospecific total synthesis of dl-pentalenolactone

Total synthesis of dl-pentalenolactone

A simple synthesis of L-.gamma.-carboxyglutamate and derivatives thereof

Methylation of nucleic acids in normal and leukemic leukocytes

Ellen Berman

Papers

A stereospecific route to aziridinomitosanes: the synthesis of novel mitomycin congeners

Stereospecific total synthesis of dl-pentalenolactone

Total synthesis of dl-pentalenolactone

A simple synthesis of L-.gamma.-carboxyglutamate and derivatives thereof

Methylation of nucleic acids in normal and leukemic leukocytes