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, Terence A Lawson, W. H. Gmeiner

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

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
Volume66
Issue number17
DOIs
StatePublished - Aug 24 2001

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Cytotoxicity
Folic Acid
Tumors
Cells
Fluorouracil
Oligodeoxyribonucleotides
Chemotherapy
Targeted drug delivery
5-fluoro-2'-deoxyuridine
Nucleotides
Messenger RNA

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Targeted drug delivery to chemoresistant cells : Folic acid derivatization of FdUMP[10] enhances cytotoxicity toward 5-fu-resistant human colorectal tumor cells. / Liu, J.; Kolar, C.; Lawson, Terence A; Gmeiner, W. H.

In: Journal of Organic Chemistry, Vol. 66, No. 17, 24.08.2001, p. 5655-5663.

Research output: Contribution to journalArticle

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