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.
Publication types
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Antineoplastic Agents / administration & dosage
-
Antineoplastic Agents / chemical synthesis*
-
Antineoplastic Agents / toxicity*
-
Carrier Proteins / biosynthesis
-
Carrier Proteins / genetics
-
Colorectal Neoplasms / drug therapy*
-
Colorectal Neoplasms / genetics
-
Colorectal Neoplasms / metabolism
-
Drug Delivery Systems
-
Drug Resistance, Neoplasm
-
Fluorodeoxyuridylate / administration & dosage
-
Fluorodeoxyuridylate / analogs & derivatives*
-
Fluorodeoxyuridylate / chemical synthesis*
-
Fluorodeoxyuridylate / toxicity*
-
Fluorouracil / pharmacology
-
Folate Receptors, GPI-Anchored
-
Folic Acid / administration & dosage
-
Folic Acid / analogs & derivatives*
-
Folic Acid / toxicity
-
Humans
-
Membrane Proteins / biosynthesis
-
Membrane Proteins / genetics
-
Membrane Transport Proteins*
-
RNA, Messenger / biosynthesis
-
RNA, Messenger / genetics
-
Receptors, Cell Surface*
-
Thymidylate Synthase / antagonists & inhibitors
-
Thymidylate Synthase / biosynthesis
-
Thymidylate Synthase / genetics
-
Tumor Cells, Cultured
Substances
-
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