title: Anti-tumor efficacy of the nucleoside analog 1-(2-deoxy-2-fluoro-4-thio-beta-D-arabinofuranosyl) cytosine (4'-thio-FAC) in human pancreatic and ovarian tumor xenograft models.
abstract: 1-(2-deoxy-2-fluoro-4-thio-beta-D-arabinofuranosyl) cytosine (4'-thio-FAC) is a deoxycytidine analog that has been shown previously to have impressive anti-proliferative and cytotoxic effects in vitro and in vivo toward colorectal and gastric tumors. In our present studies, the pharmacokinetic behavior in nude mice and the effectiveness of 4'-thio-FAC against human pancreatic and ovarian tumor growth were assessed in comparison with standard chemotherapeutic agents. Potent in vitro anti-proliferative effects were observed against pancreatic (Capan-1, MIA-PaCa-2, BxPC-3) and ovarian (SK-OV-3, OVCAR-3, ES-2) cancer cell lines with IC(50) of 0.01-0.2 microM. In vivo anti-tumor activity was evaluated in nude mice bearing subcutaneously (s.c.) implanted human pancreatic tumor xenografts or intraperitoneally (i.p.) disseminated human ovarian xenografted tumors. Oral daily administration of 4'-thio-FAC for 8-10 days significantly inhibited the growth of gemcitabine-resistant BxPC-3 pancreatic tumors and induced regression of gemcitabine-refractory Capan-1 tumors. 4'-Thio-FAC was also a highly effective inhibitor of ovarian peritoneal carcinomatosis. In the SK-OV-3 and ES-2 ovarian cancer models, 4'-thio-FAC prolonged survival to a greater extent than that observed with gemcitabine. Furthermore, the superiority of 4'-thio-FAC to carboplatin and paclitaxel was demonstrated in the ES-2 clear cell ovarian carcinoma model. Studies provide evidence that 4'-thio-FAC is a promising new alternative to gemcitabine and other chemotherapeutic drugs in the treatment of a variety of tumor indications, including pancreatic and ovarian carcinoma.
authors.affiliation: Department of Cancer Research, Berlex Biosciences, Richmond, CA 97808, USA. Deb_zajchowski@berlex.com
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Zajchowski
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Biroc
authors.forename: Hsaio-Lai
authors.initials: HL
authors.lastname: Liu
authors.forename: Steven K
authors.initials: SK
authors.lastname: Chesney
authors.forename: Jens
authors.initials: J
authors.lastname: Hoffmann
authors.forename: John
authors.initials: J
authors.lastname: Bauman
authors.forename: Thomas
authors.initials: T
authors.lastname: Kirkland
authors.forename: Babu
authors.initials: B
authors.lastname: Subramanyam
authors.forename: Jun
authors.initials: J
authors.lastname: Shen
authors.forename: Elena
authors.initials: E
authors.lastname: Ho
authors.forename: Jih-Lie
authors.initials: JL
authors.lastname: Tseng
authors.forename: Harald
authors.initials: H
authors.lastname: Dinter
mesh_terms: D000818:Animals; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology / Q000662:veterinary; D003561:Cytarabine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000662:veterinary; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000662:veterinary; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: C114001:1-(2-deoxy-2-fluoro-4-thio-arabinofuranosyl)cytosine; D003561:Cytarabine