Targeted drug delivery to chemoresistant cells: Folic acid derivatization of FdUMP[10] enhances cytotoxicity toward 5-fu-resistant human colorectal tumor cells

J. Liu, C. Kolar, T. A. Lawson, W. H. Gmeiner

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58 Scopus citations


Current chemotherapy protocols that include fluoropyrimidines, such as 5-fluorouracil (5-FU), are limited by the development of chemoresistance during the course of treatment. Our laboratory has developed a novel class of fluoropyrimidines, FdUMP[N], that are oligodeoxynucleotides (ODNs) composed of some number, N, of 5-fluoro-2′- deoxyuridine-5′-O-monphosphate (FdUMP) nucleotides. Novel synthetic procedures are described that permit conjugation of folic acid to the 5′-OH of FdUMP[10] via a phosphodiester linkage using automated synthesis. The synthetic methods developed are generally applicable for ODN conjugation with folic acid. The folic acid conjugate FA-FdUMP[10] showed improved cytotoxicity toward human colorectal tumor cells (H630), and 5-FU-resistant colorectal tumor cells (H630-10). Enhanced cytotoxicity was observed for FAFdUMP[10] relative to nonconjugated FdUMP[10] for cells grown under folate-restricted conditions, consistent with cellular uptake being, in part, receptor-mediated. Folate receptor α (FRα) mRNA was shown by RT-PCR to be overexpressed 26.3-fold in 5-FU-resistant H630-10 cells relative to H630 cells. Thus, FA-FdUMP[N] may prove useful for the treatment of 5-FU-resistant malignancies.

Original languageEnglish (US)
Pages (from-to)5655-5663
Number of pages9
JournalJournal of Organic Chemistry
Issue number17
Publication statusPublished - Aug 24 2001


ASJC Scopus subject areas

  • Organic Chemistry

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