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.
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Takahashi T, Kanazawa J, Akinaga S, Tamaoki T, Okabe M
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.
Cancer Chemother Pharmacol. 1999;43(3):233-40.
- PubMed ID
- 9923554 [ View in PubMed]
- Abstract
2-Chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) adenine (Cl-F-araA) is a novel deoxyadenosine analog, which inhibits DNA synthesis by inhibiting DNA polymerase alpha and ribonucleotide reductase. Cl-F-araA shows potent antiproliferative activity against several leukemic cell lines including those of human origin and is also effective against murine solid tumors, in particular being curative against colon tumors. PURPOSE: We therefore decided to investigate whether Cl-F-araA is effective against human colon tumors, in particular by oral administration, since it has improved stability compared with other deoxyadenosine analogs. METHODS: Antiproliferative activity in vitro was determined from cell counts. Subcutaneously inoculated xenograft models and a liver micrometastases model were used for assessment of antitumor activity in vivo. RESULTS: Cl-F-araA showed potent antiproliferative activity against four human colon tumor cell lines (HCT116, HT-29, DLD-1, WiDr), with a 50% growth-inhibitory concentration (IC50) of 0.26 microM with a 72-h exposure. This activity was greater than those of fludarabine desphosphate and cladribine, other deoxyadenosine analogs, which showed IC50 values of 19 microM and 0.35 microM, respectively. Cl-F-araA showed potent antitumor activity against four human colon tumor xenograft models (HT-29, WiDr, Co-3, COLO-320DM) in a 5-day daily administration schedule, which was shown to be the most effective of three administration regimens tested (single, twice-weekly, 5-day daily). In particular, oral administration showed significantly superior activity, with a regressive or cytostatic growth curve, compared with intravenous administration. In addition, Cl-F-araA was effective at only one-sixteenth of the maximum dose tested in a 10-day daily administration schedule. Therapeutic efficiency seemed to increase in proportion to the frequency of administration. Cl-F-araA also decreased liver micrometastases created by intrasplenic injection of human colon tumor cells, leading to complete suppression at the maximum dose tested. CONCLUSIONS: These results suggest that Cl-F-araA might be clinically effective against human colon cancers using a daily oral administration schedule.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Cladribine DNA polymerase alpha catalytic subunit Protein Humans YesInhibitorDetails Cladribine Ribonucleoside-diphosphate reductase large subunit Protein Humans YesInhibitorDetails Cladribine Ribonucleoside-diphosphate reductase subunit M2 Protein Humans YesInhibitorDetails Cladribine Ribonucleoside-diphosphate reductase subunit M2 B Protein Humans YesInhibitorDetails