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.
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.
Zajchowski
Deborah A
DA
Department of Cancer Research, Berlex Biosciences, Richmond, CA 97808, USA. Deb_zajchowski@berlex.com
Biroc
Sandra L
SL
Liu
Hsaio-Lai
HL
Chesney
Steven K
SK
Hoffmann
Jens
J
Bauman
John
J
Kirkland
Thomas
T
Subramanyam
Babu
B
Shen
Jun
J
Ho
Elena
E
Tseng
Jih-Lie
JL
Dinter
Harald
H
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
C114001:1-(2-deoxy-2-fluoro-4-thio-arabinofuranosyl)cytosine; D003561:Cytarabine