[Proceedings of the 11th NCI · EORTC · AACR Symposium]
Copyright © 2000 Stichting NCI-EORTC Symposium on New Drugs in Cancer Therapy
Published by the AACR.
125 Folic acid conjugation of multimeric FdUMP enhances cytotoxicity toward 5-FU-resistant tumor cells. William H. Gmeiner1 and Jinqian Liu2. 1Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC 27157 USA 2Tularek Corp. South San Francisco, CA USA.
Human colorectal tumor (H630-10) cells adapted to medium containing 10 µM 5-FU were shown to have elevated expression not only of thymidylate synthase (TS) mRNA (2.3-fold), but also of folate receptor -isoform (FR) mRNA (26.3-fold). Correlated overexpression of TS and FR in 5-FU-resistant tumor cells presents an opportunity for selective targeting of resistant tumor cells by conjugation of anticancer drugs with folic acid. Our laboratory has developed a novel fluoropyrimidine, FdUMP[N], that is an oligodeoxynucleotide (ODN) composed of some number, N, of FdUMP nucleotides. Targeting FdUMP[10] to 5-FU-resistant tumor cells has been achieved by covalent attachment of folic acid (FA-FdUMP[10]). The synthetic methods developed are generally applicable for ODN conjugation with folic acid. The relative cytoxicities of FA-FdUMP[10], FdUMP[10] and 5-FU towards H630 and H630-10 cells under normal and folate-deprived conditions were measured using a clonogenic assay. FdUMP[10] was considerably more cytoxic than 5-FU towards both cell lines under all conditions (10,000- 100,000-fold). FA-FdUMP[10] showed enhanced cytotoxicity relative to FdUMP[10] towards both cell lines (10-fold). A further enhancement (25-fold) of cytotoxicity towards H630-10 cells for FA-FdUMP[10], relative to FdUMP[10], was realized under conditions of folate deprivation. The results are consistent with folic acid competing with FA-FdUMP[10] for cellular uptake, and demonstrate the potential utility of FA-FdUMP[10] for treatment of 5-FU-resistant tumors. |
