Antitumor activity of 2-chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) adenine, a novel deoxyadenosine analog, against human colon tumor xenografts by oral administration

2-Chloro-9-(3-deoxy-2-fluoro-beta-D-arabinofuranosyl) adenine (C1-F-araA) i s a novel deoxyadenosine analog, which inhibits DNA synthesis by inhibiting DNA polymerase alpha and ribonucleotide reductase. C1-F-araA shows potent antiproliferative activity against several leukemic cell lines including th ose of human origin and is also effective against murine solid tumors, in p articular being curative against colon tumors. Purpose: We therefore decide d to investigate whether C1-F-araA is effective against human colon tumors, in particular by oral administration, since it has improved stability comp ared with other deoxyadenosine analogs. Methods: Antiproliferative activity in vitro was determined from cell counts. Subcutaneously inoculated xenogr aft models and a liver micrometastases model were used for assessment of an titumor activity in vivo. Results: C1-F-araA showed potent antiproliferativ e activity against four human colon tumor cell lines (HCT116, HT-29, DLD-1, WiDr), with a 50% growth-inhibitory concentration (IC50) of 0.26 mu M with a 72-h exposure. This activity was greater than those of fludarabine desph osphate and cladribine, other deoxyadenosine analogs, which showed IC50 val ues of 19 mu M and 0.35 mu M, respectively. C1-F-araA showed potent antitum or activity against four human colon tumor xenograft models (HT-29, WiDr, C o-3, COLO-320DM) in a 5-day daily administration schedule, which was shown to be the most effective of three administration regimens tested (single, t wice-weekly, 5-day daily). In particular, oral administration showed signif icantly superior activity, with a regressive or cytostatic growth curve, co mpared with intravenous administration. In addition, C1-F-araA was effectiv e at only one-sixteenth of the maximum dose tested in a 10-day daily admini stration schedule. Therapeutic efficiency seemed to increase in proportion to the frequency of administration. C1-F-araA also decreased liver micromet astases created by intrasplenic injection of human colon tumor cells, leadi ng to complete suppression at the maximum dose tested. Conclusions: These r esults suggest that C1-F-araA might be clinically effective against human c olon cancers using a daily oral administration schedule.