Enhanced antitumor activity of 6-hydroxymethylacylfulvene in combination with irinotecan and 5-fluorouracil in the HT29 human colon tumor xenograft model

6-Hydroxymethylacylfulvene (MGI-114) is a semisynthetic analogue of the tox in illudin S, a product of the Omphalotus mushroom. MGI-114 induces cytotox icity in a variety of solid tumors in vivo, including the refractory HT29 h uman colon cancer xenograft, In this study, the potential application of MG I-114 in the treatment of colon cancer was further explored by evaluating t he activity of MGI-114 in combination with irinotecan (CPT-11) and 5-fluoro uracil (5FU). Groups of 9 nude mice bearing HT29 xenografts were treated wi th either single agent MGI-114, CPT-11, or 5FU, or MGI-114 in combination w ith CPT-11 or 5FU, MGI-114 was administered at doses of 3.5 and 7 mg/kg i,p , daily on days 1 through 5, and CPT-11 and 5FU were administered at doses of 50 and 100 mg/kg i,p, on days 1, 12, and 19, In the single agent studies , MGI-114, CPT-11, and 5FU all resulted in decreased final tumor weights co mpared with vehicle-treated controls (P < 0.05), but only MGI-114 at 7 mg/k g produced partial responses, When MGI-114 at 3.5 mg/kg was combined with C PT-11, significant decrements in final tumor weights occurred compared with monotherapy with the same doses of MGI-114 and CPT-11 (P less than or equa l to 0.001). Also, administration of the low-dose combination (MGI-114 at 3 .5 mg/kg and CPT-11 at 50 mg/kg) resulted in final tumor weights similar to those achieved after administration of high-dose MGI-114 as a single agent . Moreover, the combination of MGI-114 and CPT-11 produced partial response s in nearly all of the animals, with some animals achieving complete respon ses. The outcome with the combination of MGI-114 and 5FU was less striking, with fewer partial responses and no complete responses. These results sugg est enhanced activity when MGI-114 is combined with CPT-11, and clinical tr ials to further evaluate this combination regimen are planned.