title: Novel prodrugs of tegafur that display improved anticancer activity and antiangiogenic properties.
abstract: New and more potent prodrugs of the 5-fluorouracyl family derived by hydroxymethylation or acyloxymethylation of 5-fluoro-1-(tetrahydro-2-furanyl)-2,4(1H,3H)-pyrimidinedione (tegafur, 1) are described. The anticancer activity of the butyroyloxymethyl-tegafur derivative 3 and not that of tegafur was attenuated by the antioxidant N-acetylcysteine, suggesting that the increased activity of the prodrug is in part mediated by an increase of reactive oxygen species. Compound 3 in an in vitro matrigel assay was found to be a more potent antiangiogenic agent than tegafur. In vivo 3 was significantly more potent than tegafur in inhibiting 4T1 breast carcinoma lung metastases and growth of HT-29 human colon carcinoma tumors in a mouse xenograft. In summary, the multifunctional prodrugs of tegafur display selectivity toward cancer cells, antiangiogenic activity, and anticancer activities in vitro and in vivo, superior to those of tegafur. 5-fluoro-1-(tetrahydro-2-furanyl)-2,4(1 H,3 H)-pyrimidinedione (tegafur, 1), the oral prodrug of 5-FU, has been widely used for treatment of gastrointestinal malignancies with modest efficacy. The aim of this study was to develop and characterize new and more potent prodrugs of the 5-FU family derived by hydroxymethylation or acyloxymethylation of tegafur. Comparison between the effect of tegafur and the new prodrugs on the viability of a variety of cancer cell lines showed that the IC50 and IC90 values of the novel prodrugs were 5-10-fold lower than those of tegafur. While significant differences between the IC50 values of tegafur were observed between the sensitive HT-29 and the resistant LS-1034 colon cancer cell lines, the prodrugs affected them to a similar degree, suggesting that they overcame drug resistance. The increased potency of the prodrugs could be attributed to the antiproliferative contribution imparted by formaldehyde and butyric acid, released upon metabolic degradation. The anticancer activity of the butyroyloxymethyl-tegafur derivative 3 and not that of tegafur was attenuated by the antioxidant N-acetylcysteine, suggesting that the increased activity of the prodrug is in part mediated by an increase of reactive oxygen species. Compound 3 in an in vitro matrigel assay was found to be a more potent antiangiogenic agent than tegafur. In vivo 3 was significantly more potent than tegafur in inhibiting 4T1 breast carcinoma lung metastases and growth of HT-29 human colon carcinoma tumors in a mouse xenograft. In summary, the multifunctional prodrugs of tegafur display selectivity toward cancer cells, antiangiogenic activity and anticancer activities in vitro and in vivo, superior to those of tegafur.
authors.affiliation: Chemistry Department, Bar-Ilan University, Ramat Gan, 52900, Israel.
authors.forename: Dikla
authors.initials: D
authors.lastname: Engel
authors.forename: Abraham
authors.initials: A
authors.lastname: Nudelman
authors.forename: Nataly
authors.initials: N
authors.lastname: Tarasenko
authors.forename: Inesa
authors.initials: I
authors.lastname: Levovich
authors.forename: Igor
authors.initials: I
authors.lastname: Makarovsky
authors.forename: Segev
authors.initials: S
authors.lastname: Sochotnikov
authors.forename: Igor
authors.initials: I
authors.lastname: Tarasenko
authors.forename: Ada
authors.initials: A
authors.lastname: Rephaeli
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D042783:Endothelial Cells / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology; D005557:Formaldehyde / Q000819:agonists / Q000037:antagonists & inhibitors; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors; D006801:Humans; D008297:Male; D008745:Methylation; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D012663:Semicarbazides / Q000494:pharmacology; D013329:Structure-Activity Relationship; D005641:Tegafur / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014470:Umbilical Cord / Q000166:cytology
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D000975:Antioxidants; D011355:Prodrugs; D012663:Semicarbazides; D005641:Tegafur; D005557:Formaldehyde; D051548:Histone Acetyltransferases; D000111:Acetylcysteine