The drive to develop improved treatments of cancer has resulted in the development of a number of strategies designed to regulate transcription. The retinoic acids represent one early target. As described in this report, our understanding of the molecular biology behind the retinoic acids is rapidly expanding and opportunities for improved treatments of cancer are thus expected. The field of histone deacetylation represents a second area receiving much interest in respect to transcriptional control. This field centers on the now generally accepted view that chromatin structure is plastic and that histone (de)acetylation regulates genome structure and hence transcription. Modifying this process by histone deacetylase (HDAC) inhibitors can therefore regulate, potentially in a highly specific manner, transcription thereby offering a much more targeted approach to cytostasis than currently available. Information relating to histone deacetylation is emerging with breathtaking rapidity with over 1 new article currently being published every day. In response to this activity we recently published one of the most comprehensive overview of the pharmaceutical potential of HDAC inhibitors to date. A second modification that is responsible for chromatin plasticity is DNA methylation. Aberrant methylation patterns have been reported in an increasing number of tumor suppressors and DNA repair genes determining carcinogenetic transformation. On the other hand, methyl-DNA binding recruits co-repressor complexes and modifies the structure of the chromatin to produce a transcriptionally silenced state. Thus the targeted use of DNA methylation inhibitors, like HDAC inhibitors, represents a promising approach to the treatment of cancer. Moreover, it has been reported that 5-aza-2'-deoxycytidine, a potent inhibitor of DNA methylation, in combination with histone deacetylase inhibitors, can produce a synergistic reactivation of tumor repressors. Canadian researchers have therefore recently investigated the in vitro antineoplastic activity of 5-aza-2'-deoxycytidine in combination with depsipeptide, a potent HDAC inhibitor, against MDA-MB-231 and MDA-MB-435 human breast carcinoma cell lines. They observed that the combination of 5-aza-2'-deoxycytidine and depsipeptide produced a synergistic antineoplastic effect against these tumor cells as compared to either agent administered alone. They also investigated the effect of this drug combination on the activation of maspin and gelsolin expression, two genes whose function is to suppress tumor metastasis. The drugs when used together reactivated both maspin and gelsolin to greater extend than when each agent was administered alone. The synergistic interaction between 5-aza-2'-deoxycytidine and depsipeptide on breast carcinoma cell lines provides a rationale to investigate this interesting drug combination in future clinical trials on patients with advanced breast cancer.

January, 2003

Adapted from Primeau et al, Int J Cancer 2003 Jan 10;103(2):177-84