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Enhanced Antitumor Activity of 6-Hydroxymethylacylfulvene in Combination with Irinotecan and 5-Fluorouracil in the HT29 Human Colon Tumor Xenograft Model¹

Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, Texas 78245-3217 [C. D. B., S. G. E., J. M., G. M., E. K. R., D. D. V. H., S. W.]; University of Texas Health Science Center at San Antonio, Department of Medicine/Medical Oncology, San Antonio, Texas 78284-7884 [S. G. H., S. W.]; and MGI Pharma, Inc., Minnetonka, Minnesota 55343-9667 [J. R. M.]

ABSTRACT

6-Hydroxymethylacylfulvene (MGI-114) is a semisynthetic analogue of the toxin illudin S, a product of the Omphalotus mushroom. MGI-114 induces cytotoxicity in a variety of solid tumors in vivo, including the refractory HT29 human colon cancer xenograft. In this study, the potential application of MGI-114 in the treatment of colon cancer was further explored by evaluating the activity of MGI-114 in combination with irinotecan (CPT-11) and 5-fluorouracil (5FU). Groups of 9 nude mice bearing HT29 xenografts were treated with either single agent MGI-114, CPT-11, or 5FU, or MGI-114 in combination with 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 compared with vehicle-treated controls (P < 0.05), but only MGI-114 at 7 mg/kg produced partial responses. When MGI-114 at 3.5 mg/kg was combined with CPT-11, significant decrements in final tumor weights occurred compared with monotherapy with the same doses of MGI-114 and CPT-11 (P 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 responses in nearly all of the animals, with some animals achieving complete responses. The outcome with the combination of MGI-114 and 5FU was less striking, with fewer partial responses and no complete responses. These results suggest enhanced activity when MGI-114 is combined with CPT-11, and clinical trials to further evaluate this combination regimen are planned.

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