Abstract
Purpose
4′-Thio-β-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 q1d×9 (daily treatment for nine consecutive days) or q4h×3/q1d×9 (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-β-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 q2d×5 (every other day for five treatments), q1d×9, and q4h×3/q1d×9 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.
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Acknowledgements
This work was supported by NCI grant PO1-CA34200. The authors gratefully acknowledge the technical assistance of the staff of the Cancer Therapeutics and Immunology Department. J. Tubbs and G. Jones assisted with data management, and K. Cornelius prepared the manuscript.
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Waud, W.R., Gilbert, K.S., Shepherd, R.V. et al. Preclinical antitumor activity of 4′-thio-β-d-arabinofuranosylcytosine (4′-thio-ara-C). Cancer Chemother Pharmacol 51, 422–426 (2003). https://doi.org/10.1007/s00280-003-0589-9
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DOI: https://doi.org/10.1007/s00280-003-0589-9