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

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 FA-FdUMP[10] relative to nonconjugated FdUMP[10] for cells grown under folate-restricted conditions, consistent with cellular uptake being, in part, receptor-mediated. Folate receptor alpha (FRalpha) 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.

• Authors: J Liu, C Kolar, T A Lawson, W H Gmeiner
• Journal: The Journal of organic chemistry (J Org Chem) Vol. 66 Issue 17 Pg. 5655-63 (Aug 24 2001) ISSN: 0022-3263 [Print] United States
• PMID: 11511236 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Carrier Proteins
• FdUMP(10)
• Folate Receptors, GPI-Anchored
• Membrane Proteins
• Membrane Transport Proteins
• RNA, Messenger
• Receptors, Cell Surface
• SLC19A2 protein, human
• Fluorodeoxyuridylate
• Folic Acid
• Thymidylate Synthase
• Fluorouracil

Topics

• Antineoplastic Agents (administration & dosage, chemical synthesis, toxicity)
• Carrier Proteins (biosynthesis, genetics)
• Colorectal Neoplasms (drug therapy, genetics, metabolism)
• Drug Delivery Systems
• Drug Resistance, Neoplasm
• Fluorodeoxyuridylate (administration & dosage, analogs & derivatives, chemical synthesis, toxicity)
• Fluorouracil (pharmacology)
• Folate Receptors, GPI-Anchored
• Folic Acid (administration & dosage, analogs & derivatives, toxicity)
• Humans
• Membrane Proteins (biosynthesis, genetics)
• Membrane Transport Proteins
• RNA, Messenger (biosynthesis, genetics)
• Receptors, Cell Surface
• Thymidylate Synthase (antagonists & inhibitors, biosynthesis, genetics)
• Tumor Cells, Cultured