Enhanced antitumour activity of 6-hydroxymethylacylfulvene in combination with topotecan or paclitaxel in the MV522 lung carcinoma xenograft model

6-hydroxymethylacylfulvene (HMAF; MGI 114, Irofulven) is a semisynthetic an alogue of the toxin illudin S, which is 3 product of the Omphalotus mushroo m. MGI 114 induces cytotoxicity against a broad range of solid tumours in v ivo, including the drug-refractory MV522 human lung cancer xenograft. In th is study, the potential application of MGI 114 in the treatment of lung can cer was explored by evaluating the activity of MGI 114 in combination with either topotecan (TPT) or paclitaxel. Groups of eight nude mice bearing MV5 22 xenografts were treated with MGI 114, TPT or paclitaxel as single agents and with MGI 114 in combination with TPT or paclitaxel. MGI 114 was admini stered at doses of 2.5 and 5.0 mg/kg intraperitoneally (i.p.) daily on days 1-5, while TPT and paclitaxel were administered at doses of 0.5 or 1.0 mg/ kg and 20 mg/kg, respectively, i.p. on days 1-5. In the single-agent studie s, MGI 114, TPT and paclitaxel all resulted in decreased final tumour weigh ts compared with vehicle-treated controls. As single agents, TPT, at the 0. 5 mg/kg dose level, and paclitaxel, at the 20 mg/kg dose level, produced pa rtial shrinkages (PSs). All combinations of MGI 114, and either TPT or pacl itaxel, produced decrements in final tumour weights compared with monothera py with the same doses of MGI 114, TPT and paclitaxel. Although all animals treated with the combination of MGI 114 and paclitaxel experienced PSs or complete shrinkages (CSs) (or died), analysis of the time to tumour doublin g revealed that the combination of MGI 114 and TPT at 2.5 and 0.5 mg/kg, re spectively, was synergistic. These results suggest that cytotoxic activity is enhanced when MGI 114 is combined with either TPT or paclitaxel, and cli nical trials to further evaluate these combination regimens are warranted. (C) 2000 Elsevier Science Ltd. All rights reserved.