Anti-tumor efficacy of the nucleoside analog 1-(2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine (4′-thio-FAC) in human pancreatic and ovarian tumor xenograft models
✍ Scribed by Deborah A. Zajchowski; Sandra L. Biroc; Hsaio-Lai Liu; Steven K. Chesney; Jens Hoffmann; John Bauman; Thomas Kirkland; Babu Subramanyam; Jun Shen; Elena Ho; Jih-Lie Tseng; Harald Dinter
- Publisher
- John Wiley and Sons
- Year
- 2005
- Tongue
- French
- Weight
- 295 KB
- Volume
- 114
- Category
- Article
- ISSN
- 0020-7136
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✦ Synopsis
Abstract
1‐(2‐Deoxy‐2‐fluoro‐4‐thio‐β‐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 μM. 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. © 2004 Wiley‐Liss, Inc.