Comparison of antitumor activity of declopramide (3-chloroprocainamide) and N-acetyl-declopramide

Previous studies have suggested that some of the antitumor activity of decl opramide (3-chloroprocainamide) could be due to its metabolites. One metabo lite has been identified as N-acetyl-declopramide (N-acetyl-3-chloroprocain amide). The aim of this study is to investigate the bioactivity of N-acetyl -declopramide and to compare it with its parent compound. The data have sho wn that N-acetyl-declopramide inhibited tumor cell growth in vitro in HL60 and K562 cells, and in vivo in scid mice xenografted with a human brain ast rocytoma (T24) which was evaluated after oral doses of 20 and 40 mg/kg give n at 0, 24 and 48 hr +/- a single im dose of cisplatin (7.5 mg/kg). The act ion was presumably by inducing DNA strand breaks and apoptosis. No acute to xic symptoms and no body weight loss were observed. N-acetyl-declopramide g iven orally or im gave a similar drug level in mouse serum 30 minutes after administration (p > 0.05). It had a greater antitumor activity in vitro in HL60 or K562 cells and a similar efficacy of inhibiting tumor growth in vi vo, when compared with declopramide. These data provided and explanation fo r the primary result obtained in this study, i.e. declopramide administered orally at 40 mg/kg gave the same efficacy of inhibiting tumor growth as im injection although oral administration had a lower bioavailability due to the formulation of N-acetyl-declopramide. Based on these data, it was concl uded that the antitumor properties of declopramide administered orally were not compromised by metabolism to N-acetyl-declopramide because the latter also has strong antitumor properties.