Relation between Irofulven (MGI-114) systemic exposure and tumor response in human solid tumor xenografts.
Irofulven is a novel, small molecular weight semisynthetic compound, derived from a family of mushroom toxins known as illudins. This DNA alkylating agent has a chemical structure unlike any other chemotherapeutic agent in clinical use. The molecule is currently being studied in several Phase I, II, and III trials. The objectives of this study were to evaluate the antitumor activity of Irofulven in a panel of 20 pediatric solid tumor xenografts and to relate the Irofulven systemic exposure, defined as area under the concentration time curve, to the antitumor dose associated with tumor regression in the tumor models. Irofulven was administered i.v. daily for 5 days with courses repeated every 21 days for a total of three cycles. The minimum effective dose of Irofulven causing objective regression (> or =50% volume regression) of advanced tumors was determined for each of 19 of 20 independently derived tumor models (12 brain tumors, 4 neuroblastomas, and 4 rhabdomyosarcomas). At the maximum tolerated dose for three cycles of treatment (4.6 mg/kg/day) objective regressions were determined in 14 of 18 tumor lines (78%). However, the dose-response relationship was acute. At 2 mg/kg only 3 of 15 tumors tested demonstrated objective regressions, and in 3 additional tumors volume regressions were not achieved at a higher dose level (3 mg/kg), hence were not additionally tested. After administering the maximum tolerated dose (tolerated for one or two cycles of treatment) of Irofulven, 7 mg/kg, to mice bearing sensitive and resistant human tumors plasma concentration-time profiles were determined. Tumors were highly sensitive to Irofulven, but the systemic exposure required for a significant rate of objective response in this panel of tumors is in excess of that achievable in patients at tolerable doses, using this schedule of drug administration.
Leggas
Markos
M
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Stewart
Clinton F
CF
Woo
Michael H
MH
Fouladi
Maryam
M
Cheshire
Pamela J
PJ
Peterson
Jennifer K
JK
Friedman
Henry S
HS
Billups
Catherine
C
Houghton
Peter J
PJ
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use; D001254:Astrocytoma / Q000188:drug therapy / Q000473:pathology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology; D002648:Child; D002851:Chromatography, High Pressure Liquid; D003520:Cyclophosphamide / Q000008:administration & dosage; D003606:Dacarbazine / Q000008:administration & dosage; D003609:Dactinomycin / Q000008:administration & dosage; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy / Q000473:pathology; D005910:Glioma / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008808:Mice, Inbred CBA; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009447:Neuroblastoma / Q000188:drug therapy / Q000473:pathology; D018242:Neuroectodermal Tumors, Primitive / Q000188:drug therapy / Q000473:pathology; D011828:Radiation Chimera; D011897:Random Allocation; D018335:Rhabdoid Tumor / Q000188:drug therapy / Q000473:pathology; D018233:Rhabdomyosarcoma, Embryonal / Q000188:drug therapy / Q000473:pathology; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D012717:Sesquiterpenes; D003609:Dactinomycin; D014750:Vincristine; C102714:irofulven; D003606:Dacarbazine; D004317:Doxorubicin; D003520:Cyclophosphamide