and progression free survival with FOLFOX4, compared to the LV5FU2 regimen . A combination of irinotecan and FL chemotherapy prolonged time to progression and progressionfree survival in metastatic colorectal cancers . Capecitabine treatment led to the exclusive accumulation of 5 FU in tumors via enzymatic activities of cytidine deaminase and thymidine phosphorylase 5-alpha-reductase in the liver and tissues, respectively . As these metabolic processes are diminished or blocked in the HDRA system, tumor growth IR with capecitabine was as low as that with 5 FU. Similarly, additive effect of irinotecan to FL, by its active metabolite of SN 38 primarily converted in the liver, was not identified in our investigation.
One study showed that SAHA inhibits the growth of pancreatic cancer cells by inducing apoptosis, cell cycle arrest, and differentiation associated with reactivation of tumor suppresser genes . In Temsirolimus the first open label, singlearm, nonrandomized study, 74 patients with advanced CTCL treated with SAHA showed approximately 30% We identified a consistent additive chemosensitivities with the combination of HDAC inhibitors to FLOX and FLIRI in the range of 19.7% to 43.8% regardless of various HDAC inhibitors, suggestive of synergistic efficacy. Moreover, these additive effects did not differ in the established regimens including 5 FU. Theoretically, the open chromatin structures caused by histone acetylation may provide additional target sites for established DNA damaging anticancer drugs. Initial gene expression studies with HDAC inhibitors led to the identification of thymidylate synthase as their target .
In vivo mouse xenograft models of colorectal dermatology cancer cell lines, HT29 and HCT116, disclosed a more significant reduction in tumor volume, following combined treatment with PXD101 and 5 FU, compared to the single compounds . Otherwise, a triple combination of SAHA, 5 FU, and irinotecan enhanced anti proliferative and apoptotic effects but not a dual combination in hepatoma cell lines . Integrative data suggest that the benefits of adding HDAC inhibitors to established regimens may depend not only on the schedule and type of drug but also specific tumor cells . However, true in vitro synergy may not confer a clinical advantage if synergistic effects are exerted to a similar extent on normal tissues and tumors.
SAHA and PXD101 are currently in clinical trials in combination with 5 FU, since HDAC inhibition results in the repression of thymidylate synthase in solid tumors. Clinicopathologic markers associated with drug response can be potentially used to facilitate individualized treatment, particularly in the absence of broadly accepted markers. Expanding tumors were closely associated with chemosensitivity to FLOX in our experiments. This phenomenon may partly depend on greater drug accessibility via abundant tumor vasculature in these tumors. An earlier report demonstrates that angiogenesis is closely associated with tumor mass expansion, which is strongly inhibited by a FU based compound . In our analyses, advanced T category tumors were more chemosensitive to CG 3, additionally to that of lymph node positive tumors to CG 2. There are currently no markers to predict responses to and roles of individual HDAC enzymes in tumor development or proliferation .