Intratumoral injection of thymidine: enhancement of the antitumor activity and incorporation of 5-fluorouracil into tumor RNA in a murine tumor system.

Intratumoral injection of thymidine (dThd) into mice bearing an Ehrlich ascites solid tumor in combination with an ip injection of 5-fluorouracil (FUra) was performed to investigate the following: (a) whether intratumoral injection of dThd would increase both the incorporation of FUra into tumor RNA and the antitumor activity of FUra as effectively as ip injection of dThd, and (b) whether intratumoral injection of dThd would have a selective advantage for increasing the incorporation of FUra into the tumor RNA, relative to normal tissue RNA. Pulse-labeling with [3H]FUra at different times after dThd injection indicated that the most effective incorporation of FUra into the tumor RNA occurred with both intratumoral and ip injection of dThd, when FUra and dThd were given simultaneously. The amount of FUra-containing RNA [(FU)RNA] was dThd dose-dependent and reached a maximum at a dThd dose of 100 mg/kg, in the case of either intratumoral or ip injection. The maximal level with intratumoral injection of dThd was twofold higher than the level with ip injection and at least fivefold higher than the level achieved with FUra alone. In a time course study, the amount of (FU)RNA formed after intratumoral injection of dThd was comparable to the level obtained with ip injection, which was fourfold to sixfold greater than that seen with FUra alone. Furthermore, in the four normal organs (bone marrow, intestine, kidneys, and lungs) the amount of (FU)RNA formed after intratumoral injection of dThd was markedly lower than the level with ip injection. Assay of FUra degradation products revealed low levels of FUra catabolism in the tumor tissue compared to liver. In addition, therapy experiments showed that the antitumor activity of FUra was increased 17-fold by coadministration of dThd by either route.