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Relation between Irofulven (MGI-114) systemic exposure and tumor response in human solid tumor xenografts.

Publication ,  Journal Article
Leggas, M; Stewart, CF; Woo, MH; Fouladi, M; Cheshire, PJ; Peterson, JK; Friedman, HS; Billups, C; Houghton, PJ
Published in: Clin Cancer Res
September 2002

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.

Duke Scholars

Published In

Clin Cancer Res

ISSN

1078-0432

Publication Date

September 2002

Volume

8

Issue

9

Start / End Page

3000 / 3007

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Vincristine
  • Tumor Cells, Cultured
  • Sesquiterpenes
  • Rhabdomyosarcoma, Embryonal
  • Rhabdoid Tumor
  • Random Allocation
  • Radiation Chimera
  • Oncology & Carcinogenesis
  • Neuroectodermal Tumors, Primitive
 

Citation

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MLA
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Leggas, M., Stewart, C. F., Woo, M. H., Fouladi, M., Cheshire, P. J., Peterson, J. K., … Houghton, P. J. (2002). Relation between Irofulven (MGI-114) systemic exposure and tumor response in human solid tumor xenografts. Clin Cancer Res, 8(9), 3000–3007.
Leggas, Markos, Clinton F. Stewart, Michael H. Woo, Maryam Fouladi, Pamela J. Cheshire, Jennifer K. Peterson, Henry S. Friedman, Catherine Billups, and Peter J. Houghton. “Relation between Irofulven (MGI-114) systemic exposure and tumor response in human solid tumor xenografts.Clin Cancer Res 8, no. 9 (September 2002): 3000–3007.
Leggas M, Stewart CF, Woo MH, Fouladi M, Cheshire PJ, Peterson JK, et al. Relation between Irofulven (MGI-114) systemic exposure and tumor response in human solid tumor xenografts. Clin Cancer Res. 2002 Sep;8(9):3000–7.
Leggas, Markos, et al. “Relation between Irofulven (MGI-114) systemic exposure and tumor response in human solid tumor xenografts.Clin Cancer Res, vol. 8, no. 9, Sept. 2002, pp. 3000–07.
Leggas M, Stewart CF, Woo MH, Fouladi M, Cheshire PJ, Peterson JK, Friedman HS, Billups C, Houghton PJ. Relation between Irofulven (MGI-114) systemic exposure and tumor response in human solid tumor xenografts. Clin Cancer Res. 2002 Sep;8(9):3000–3007.

Published In

Clin Cancer Res

ISSN

1078-0432

Publication Date

September 2002

Volume

8

Issue

9

Start / End Page

3000 / 3007

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Vincristine
  • Tumor Cells, Cultured
  • Sesquiterpenes
  • Rhabdomyosarcoma, Embryonal
  • Rhabdoid Tumor
  • Random Allocation
  • Radiation Chimera
  • Oncology & Carcinogenesis
  • Neuroectodermal Tumors, Primitive