Preclinical antitumor activity of 4'-thio-beta-D-arabinofuranosylcytosine (4'-thio-ara-C).
OBJECTIVE
4'-Thio-beta -d-arabinofuranosylcytosine (4'-thio-ara-C), which has shown significant cytotoxicity against a panel of human tumor lines, was evaluated for antitumor activity against a spectrum of human tumor systems in mice.


METHODS
Antitumor activity was evaluated in 15 subcutaneously implanted human tumor xenografts. 4'-Thio-ara-C was administered intraperitoneally using either q1dx9 (daily treatment for nine consecutive days) or q4hx3/q1dx9 (three treatments each day separated by 4-h intervals for nine consecutive days).


RESULTS
4'-Thio-ara-C exhibited an excellent spectrum of activity. Treatment with the compound was curative against HCT-116 colon, SW-620 colon, NCI-H23 NSCL, and CAKI-1 renal tumors and resulted in partial/complete regressions in the DLD-1 colon, NCI-H522 NSCL, DU-145 prostate, and PANC-1 pancreatic tumor models. Tumor stasis was noted for HT29 colon and NCI-H460 NSCL tumors. Tumor inhibition was observed for A549 NSCL, PC-3 prostate, LNCAP prostate, and MDA-MB-435 breast tumors. Of the 15 tumors examined, only CFPAC-1 pancreatic was unresponsive to the compound. In contrast, 1-beta -d-arabinofuranosylcytosine was minimally active at best against CAKI-1 renal, HCT-116 colon, NCI-H460 NSCL, and SW-620 colon tumors. Schedule- and route-dependency studies were conducted using the NCI-H460 NSCL tumor. The activity of 4'-thio-ara-C was independent of schedule when comparing q2dx5 (every other day for five treatments), q1dx9, and q4hx3/q1dx9 treatment schedules. 4'-Thio-ara-C was equally effective by the intravenous and intraperitoneal routes of administration, with the oral route being less efficacious.


CONCLUSIONS
On the basis of these results, 4'-thio-ara-C appears to have a profile distinct from other nucleoside antitumor agents and is being advanced to clinical trials.
Waud
William R
WR
Cancer Therapeutics and Immunology Department, Southern Research Institute, Birmingham, Alabama 35255, USA. waud@sri.org
Gilbert
Karen S
KS
Shepherd
Rodney V
RV
Montgomery
John A
JA
Secrist
John A
JA
D000818:Animals; D001087:Arabinonucleosides / Q000494:pharmacology*; D004334:Drug Administration Schedule; D004354:Drug Screening Assays, Antitumor; D007263:Infusions, Parenteral; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy*; D014183:Transplantation, Heterologous
D001087:Arabinonucleosides; C411255:4'-thio-arabinofuranosylcytosine