Symadex is in phase 1 for the treatment of solid tumors and shows considerable activity in preclinical colorectal cancer models. We investigated the combination of Symadex with other agents currently approved or under development for treatment of colorectal cancer. Symadex was combined with the anticancer drugs; irinotecan, oxaliplatin, 5-fluourouracil (5-FU), Xanafide & etoposide). The combinations were used to treat two colorectal cell lines (HT29 & HCT116) in vitro. The agents were individually tested using 5 day exposures to determine their GI50’s. Symadex is the most active agent on both cell lines. The agents were then combined using fixed GI50’s with variable concentrations (10-13 to 10-5 M) of the paired drug to enable testing of various drug ratios. The combinations of Symadex with irinotecan, oxaliplatin and etoposide were not synergistic in both cell lines tested. The combinations of GI50 Symadex with varying concentrations of Xanafide or 5-FU were also not synergistic. However, the combinations of GI50 Xanafide or 5-FU with varying concentrations of Symadex were both highly synergistic. At non-therapeutic doses of Symadex the Xanafide and 5-FU induced growth inhibition increased from the expected 50% to > 80%. The observed synergy of Symadex and 5-FU is particularly interesting as it may apply to a combination of Symadex with Xeloda for colorectal cancer. As Xeloda is not activated in vitro, 5-FU was used as a surrogate. These current results indicate that the combinations of Symadex with Xanafide or 5-FU may be active regimens in the treatment of colon cancer.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]