Combination therapy with radiation, mitomycin C, and 5-fluorouracil in EMT6 tumors

The primary purpose of these studies was to assess whether concomitant treatment with 5-fluorouracil increased the cytotoxicity of radiation, mitomycin C, or the combination of these two agents to cells in solid tumors.

All studies were performed using EMT6 mouse mammary tumor cells. In vitro studies used exponentially-growing monolayers. In vivo studies used solid EMT6 tumors growing in BALB/c Rw mice. The effects of treatment on tumors or cultures were assessed using clonogenic assays which considered both the colony forming abilities of the intact cells and the numbers of cells in the cultures or tumors.

EMT6 cells in vitro were killed effectively by 5-fluorouracil. The cytotoxicity increased as the drug concentration increased from 1 microM to 1 mM or as the treatment time increased from 1 to 48 hr. However, 5-fluorouracil was only marginally active against solid EMT6 tumors: treatment with doses of up to 400 micrograms/gm killed less than 50% of the tumor cells, regardless of whether the drug was given as an injection or an infusion over 48 hr and regardless of the time between injection of the drug and assay of cell survival. Treatment with 5-fluorouracil produced only a statistically insignificant increase in the effect of 15 Gy of x-rays, whether the drug was given by injection or infusion over 48 hr. Both injection of 200 micrograms/g 5 FU and infusion of 100 micrograms/g 5-fluorouracil decreased the cytotoxicity of 6 micrograms/g of MC to cells in solid tumors. Injection of 200 micrograms/g of 5-fluorouracil decreased the cytotoxic effects of a regimen combining 6 micrograms/g MC plus 15 Gy of x-rays.

In this solid tumor system, a regimen combining single doses of mitomycin C and x-rays was more effective in killing the tumor cells than was the same regimen combined with 5-fluorouracil.