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Figure 2. Chemical structures of azacitidine and decitabine. Azacitidine is metabolized intracellularly into decitabine

promoter hypermethylation of BRCA1 (10%). Homologous recombination deficiency may also result from
PTEN homozygous loss, detected in about 7% of HGSOC .
[59]

DNA METHYLATION
Epigenetic gene silencing is increasingly being recognized to contribute to the development of cis- and
carboplatin resistance. Auspiciously, the treatment with demethylating agents has been shown to re-sensitize
patients to platinum therapy demonstrating that DNA methylation is a critical factor in drug resistance.
The most important DNA methyltransferase (DNMT) inhibitors are azacitidine and decitabine (5-aza-2′-
deoxycytidine, dacogen). They are hypomethylating analogues of cytidine [Figure 2], and commonly used to
treat myelodysplastic, hematological malignancies. Azacitidine was the first drug to demonstrate a survival
benefit in a randomized trial for patients with myelodysplastic syndromes [60,61] . The following paragraphs
give an overview on methylated genes that affect chemo-resistance.

Cisplatin resistance
In ovarian cancer, selective epigenetic alterations of distinct biological pathways have been observed during
development of platinum resistance. Hypermethylation-mediated repression of cell adhesion and tight
junction pathways as well as hypomethylation-mediated activation of the cell growth-promoting pathways
PI3K/Akt and TGF-β may contribute to platinum resistance . As the following in vitro and in vivo studies
[62]
demonstrate, chemo-resistance may be reversible by alteration of DNA methylation which may be an effective
strategy to enhance the effectiveness of chemotherapeutic treatment in ovarian cancer.

High expression of DNMT1 is detected in S-phase of the cell cycle and makes DNMT1 a specific target for DNA
methylation inhibition in rapidly dividing cancer cells. Covalent binding of DNMT1 by the nucleoside analogue
SGI-110 results in DNMT1 proteolysis . To assess the effects of SGI-110 on chemo-responsive genes silenced
[63]
by DNA methylation in ovarian cancer, Fang et al. applied pyrosequencing. In vitro, they demonstrated that
[21]
SGI-110 re-sensitized a range of cisplatin-resistant ovarian cancer cells, and induced significant demethylation
and re-expression of tumor suppressor genes, differentiation-associated genes and even, putative drivers of
ovarian cancer cisplatin resistance. In vivo, pyrosequencing of ovarian cancer xenografts confirmed that
SGI-110 caused both global (LINE1 repetitive sequences) and gene-specific hypomethylation, including the
tumor suppressor gene Ras Association Domain Family 1 (RASSF1A), the assumed drivers of ovarian cancer
cisplatin resistance and the zinc finger protein ZIC1, the differentiation-associated genes HOXA10 and HOXA11
and the transcription factor STAT5B, as well as the DNA mismatch repair gene MLH1. The methylation of
MLH1 in resistant cells has been investigated by several laboratories. Using genome-wide DNA methylation
profiling, Zeller et al. identified genes becoming hypermethylated in chemo-resistant ovarian cancer cells.
[22]
In particular, they found that MLH1 had a direct role in conferring cisplatin sensitivity when reintroduced