5-Azactydine inhibits cell growth by direct cytotoxic action as well as by 
inhibition of DNA methyl transferase enzyme. Inhibitors of DNMT have been 
reported to potentiate the therapeutic activity of cisplatin in vitro. Dose 
dependent bone marrow toxicity, neurotoxicity and nephrotoxicity are the major 
side effects of cisplatin, limiting its use as an effective chemotherapeutic 
agent. The present study was aimed to reduce the nephrotoxic potential of 
cisplatin without compensating its potency. To best of our knowledge, this is 
the first report which shows that the combination of 5-azacytidine with 
cisplatin leads to remarkable reduction in nephrotoxicity, by involving 
inhibition of cisplatin induced metallothionein expression. 5-Azacytidine 
treatment with cisplatin leads to maximum reduction in tumor size in DMH induced 
colon cancer and tumor volume in DMBA induced breast cancer bearing SD rats. 
This combination regimen prevents phosphorylation and acetylation of histone H3 
which may be involved in inhibition of aberrant gene expression in colon tumors. 
Further, 5-azacytidine potentiated cisplatin induced antitumor activity by 
involving decreased expression of pAKT, DNMT1 and an increased expression of p38 
in colon tumors. Thus, combination of 5-azactydine with cisplatin attenuates the 
cisplatin induced nephrotoxicity and potentiates the anti-cancer activity which 
can have profound clinical implications.