TY - JOUR
T1 - MGI 114
T2 - Augmentation of antitumor activity when combined with topotecan
AU - Weitman, Steven
AU - Barrera, Hector
AU - Moore, Rodney
AU - Gonzalez, Cristina
AU - Marty, Jennifer
AU - Hilsenbeck, Susan
AU - MacDonald, John R.
AU - Waters, Stephen J.
AU - Von Hoff, Daniel
PY - 2000/1/1
Y1 - 2000/1/1
N2 - Purpose: 6-Hydroxymethylacylfulvene (HMAF; MGI 114; Irofulven) is a semisynthetic 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 µg/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.
AB - Purpose: 6-Hydroxymethylacylfulvene (HMAF; MGI 114; Irofulven) is a semisynthetic 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 µg/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.
KW - HMAF
KW - Illudins
KW - MGI 114
KW - Pediatric oncology
KW - Synergy
UR - http://www.scopus.com/inward/record.url?scp=0034456925&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034456925&partnerID=8YFLogxK
U2 - 10.1097/00043426-200007000-00006
DO - 10.1097/00043426-200007000-00006
M3 - Article
C2 - 10959900
AN - SCOPUS:0034456925
SN - 1077-4114
VL - 22
SP - 306
EP - 314
JO - Journal of Pediatric Hematology/Oncology
JF - Journal of Pediatric Hematology/Oncology
IS - 4
ER -