MGI 114: Augmentation of antitumor activity when combined with topotecan

Purpose: 6-Hydroxymethylacylfulvene (HMAF: MGI 114: Irofulven) is a semis;nthetic analogue of the mushroom toxin illudin S that has been shown to be a potent cytotoxic agent with an improved therapeutic index compared with its parent compound. The studies were conducted to evaluate the antitumor activity of MGI 114 as a single agent and in combination with topotecan against pediatric solid tumor cell lines and xenograft models. Materials and Methods: in vitro studies were designed to determine the cytotoxic potential of MGI 114 using the MTT assay and 13 pediatric tumor cell lines. In addition, combination in vitro studies were performed with MGI 114 and topotecan to generate isoeffect plots, single agent and combination in vivo studies were also performed using MGI 114 against rhabdomyosarcoma and neuroblastoma xenograft models. Results: After a 1-hour exposure to MGI 114, the mean IC50 (+/- standard error of mean) for medulloblastoma, neuroblastoma, Ewing sarcoma/primitive neuroectodermal tumor, and rhabdomyosarcoma cell lines were 1.58 +/- 0.51, 1.60 +/- 0.82, 1.18 +/- 0.08, and 3.99 +/- 1.69 mu g/mL, respectively. When tumor cells were exposed concurrently to MGI 114 and topotecan, evidence of synergy was observed in 10 of 12 (83%) cell lines. single agent and combination in vivo studies with MGI 114 showed that this agent had substantial, and at times curative, antitumor activity against rhabdomyosarcoma and neuroblastoma xenograft tumors. Conclusions: These data suggest that MGI 114 has significant efficacy as a single agent in preclinical studies against pediatric tumors. In addition, based on previous reports and the results presented here, combining MGI 114 with topotecan appears to be an attractive approach to the treatment of pediatric malignancies. After completion of the pediatric phase I studies of MGI 114, consideration should be given to phase II single agent and phase I combination studies with a topoisomerase I inhibitor such as topotecan or irinotecan.