As treatment of cells with the PEP downregulated TS and TK due to inhibition of E2F-1 expression [19], it was of interest to determine if treatment of tumor cells with the combination of the D-Arg PEP and pemetrexed, a potent thymidylate synthase inhibitor [25,26], would result in additive or synergistic antitumor effect. This evidence concerns the gene E2F1 and neoplasm.