Targeted drug delivery to chemoresistant cells: folic acid derivatization of FdUMP[10] enhances cytotoxicity toward 5-FU-resistant human colorectal tumor cells.
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.
Liu
J
J
Eppley Institute, University of Nebraska Medical Center, Omaha, Nebraska 68198-6805, USA.
Kolar
C
C
Lawson
T A
TA
Gmeiner
W H
WH
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000633:toxicity*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D005468:Fluorodeoxyuridylate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000633:toxicity*; D005472:Fluorouracil / Q000494:pharmacology; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D026901:Membrane Transport Proteins; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011956:Receptors, Cell Surface; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002352:Carrier Proteins; C435305:FdUMP(10); D058973:Folate Receptors, GPI-Anchored; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C120043:SLC19A2 protein, human; D005468:Fluorodeoxyuridylate; D005492:Folic Acid; D013940:Thymidylate Synthase; D005472:Fluorouracil