The combined use of 2′-deoxy-5-azacytidine with cisplatin or 4-hydroperoxycyclophosphamide in vitro frequently resulted in synergistic cytotoxicity against a panel of six human cell lines. This enhanced cell killing occurred at drug concentrations that are clinically achievable. Synergy was also seen if the sequence of drug administration was altered, implying that a temporal overlap between the drugs was necessary, but that the actual biochemical lesions induced by each agent were probably unique, and interacted in an as yet undefined manner. Of further interest was the observation that at least one of the synergistic pairs was active against five of the six cell lines tested. 2′-Deoxy-5-azacytidine incorporation as assessed by the level of gross genomic DNA methylation did not appear to correlate with the synergistic cytotoxicity observed. Thus, we could not discern a clear relationship between the degree of DNA hypomethylation and the observed synergies, although DNA hypomethylation frequently occurred when synergy was demonstrated. The practical usefulness of these drug combinations has not yet been tested and awaits appropriate clinical trials both to assess the tumoricidal effects and possible increased toxicity.
Supported in part by Grants CA-39853 and 41525 from the USPHS and the University of Texas M. D. Anderson Cancer Center.