Can the combination of 5-fluorouracil and gemcitabine increase the treatment efficacy of pancreatic and colon cancer?

Pancreatic ductal adenocarcinoma (PDAC) is intrinsically drug-resistant. Combinations of 5-fluorouracil (5-FU) with other cytostatics in FOLFIRINOX and gemcitabine (Gem) with nab-paclitaxel are first-line treatments. Colorectal cancer (CRC) is treated with FOLFOX or FOLFIRI, but in advanced disease patients become resistant for whom Gem has been considered. We investigated whether combining the key drugs, 5-FU and Gem, would be advantageous with different treatment schedules. We used CRC (human WiDr cells and Colon 26-A, a syngeneic mouse tumor) and a murine PDAC (PANC02 cells and tumors) as well-defined model systems. In WiDr at 3-day simultaneous exposure, the 5-FU and Gem combination was antagonistic, while in PANC02 cells it was additive at simultaneous addition, but synergistic when Gem was added 6 hr after 5-FU. The antagonism might relate to the decrease in FdUMP concentration (about 50%) caused by Gem. Based on these data, we initiated an in vivo study with Gem administered after 5-FU. Since 5-FU is more effective as a prolonged infusion, we used 5-FU pellets, implanted subcutaneously, to deliver 5-FU for 5 days. Gem was given at q3dx4. The 2.5 mg 5-FU infusion with 75 mg/kg Gem was most optimal with tolerable weight loss (<10%). The tumor size of treated vs control tumors (T/C) at this schedule for CRC was 0.49 for 5-FU alone, 0.21 for Gem alone, and 0.16 for the combination. For PDAC, these values were 0.77, 0.74, and 0.49, respectively. In conclusion, unfortunately, the efficacy of the combination of 5-FU with gemcitabine was moderate, both in vitro and in vivo.