DIFFERENCES IN RESISTANCE TO 5-FLUOROURACIL AS A FUNCTION OF CELL-CYCLE DELAY AND NOT APOPTOSIS

A series of human embryo fibroblasts has previously been shown to disp lay increasing resistance to the antimetabolites methotrexate (MTX) an d N-phosphonacetyl-L-aspartate (PALA) with increasing tumorigenicity. This increased resistance was found to be further increased as a resul t of salvage pathway activity for purine and pyrimidine biosynthesis. A similar pattern of increasing resistance paralleling increasing tumo rigenicity has now been shown to occur with 5-fluorouracil (5-FU), whi ch is independent of salvage pathway activity. The KMS normal cell lin e was found to be more sensitive to 5-FU than either the immortalised KMST or tumorigenic KN-NM cell lines. Immunohistochemical analysis of the three cell lines demonstrated high levels of p53 protein in the KM ST and KN-NM cell lines, but undetectable p53 levels in the KMS cell l ine. From these data it was hypothesised that a difference in p53 func tion may be causing the difference in the patterns of sensitivity obse rved in the three cell lines. P53 is now believed to function as a reg ulator of a G(1) to S cell cycle checkpoint and as an inducer of apopt osis following DNA damage to the cell. The differences in sensitivity of the cell lines could not be explained by differences in the levels of apoptosis but could be attributed to differences in cell cycle resp onse. Our evidence suggests that loss of cell cycle control, possibly through loss of p53 function, is an important factor in increasing the drug resistance of fibroblast cell lines.