Improving the anti-tumor activity of 5-fluorouracil by increasing its incorporation into RNA via metabolic modulation.

Abstract

The experiments described here illustrate the use of metabolic modulation to improve the therapeutic effectiveness of 5-fluorouracil (5FUra) in two murine tumor systems (CD8F1 mannary carcinoma and CD2F1 colon tumor 26). The manipulations chosen were based on the assumption that a major fraction of the anti-tumor activity of 5FUra is due to its incorporation into RNA and that the resulting 5FUra-RNA creates difficulty for a variety of cellular mechanisms requiring RNA processing and function. This hypothesis leads to the prediction that thymidine would promote the anti-neoplastic effect of 5FUra due to the following possible interactions: (i) sparing 5FUra from catabolic degradation by saturating the relevant enzymes wit thymidine; (ii) selective arrest of normal cells due to feedback inhibition of robonucleotide reductase by the accumulating thymidine triphosphate (TTP); and (iii) the high levels of TTP would also be expected to repress the anabolic conversion of 5FUra to the deoxy derivatives, thus preserving it for entry into RNA. The data show that thymidine (and certain other nucleosides) does in fact markedly stimulate the incorporation of 5FUra into nuclear RNA and that this event is paralleled by a striking icrease in anti-tumor activity. Kinetic analysis reveals that, although the injection of 5FUra leads to an immediate cessation of thymidylate synthetase activity, DNA synthesis continues at a lower rate for 12 hr and then ceases completely. At this point, in contrast to the earlier partial inhibition, the addition of thymidine fails to restore the ability of the tumor cells to synthesize DNA.