Enhanced antitumour activity of 6-hydroxymethylacylfulvene in combination with topotecan or paclitaxel in the MV522 lung carcinoma xenograft model

L. A. Hammond, S. G. Hilsenbeck, S. G. Eckhardt, J. Marty, G. Mangold, J. R. MacDonald, E. K. Rowinsky, D. D. Von Hoff, Steven D Weitman

Research output: Contribution to journalArticle

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Abstract

6-Hydroxymethylacylfulvene (HMAF; MGI 114; Irofulven) is a semisynthetic analogue of the toxin illudin S, which is a product of the Omphalotus mushroom. MGI 114 induces cytotoxicity against a broad range of solid tumours in vivo, including the drug-refractory MV522 human lung cancer xenograft. In this study, the potential application of MGI 114 in the treatment of lung cancer was explored by evaluating the activity of MGI 114 in combination with either topotecan (TPT) or paclitaxel. Groups of eight nude mice bearing MV522 xenografts were treated with MGI 114, TPT or paclitaxel as single agents and with MGI 114 in combination with TPT or paclitaxel. MGI 114 was administered at doses of 2.5 and 5.0 mg/kg intraperitoneally (i.p.) daily on days 1-5, while TPT and paclitaxel were administered at doses of 0.5 or 1.0 mg/kg and 20 mg/kg, respectively, i.p. on days 1-5. In the single-agent studies, MGI 114, TPT and paclitaxel all resulted in decreased final tumour weights compared with vehicle-treated controls. As single agents, TPT, at the 0.5 mg/kg dose level, and paclitaxel, at the 20 mg/kg dose level, produced partial shrinkages (PSs). All combinations of MGI 114, and either TPT or paclitaxel, produced decrements in final tumour weights compared with monotherapy with the same doses of MGI 114, TPT and paclitaxel. Although all animals treated with the combination of MGI 114 and paclitaxel experienced PSs or complete shrinkages (CSs) (or died), analysis of the time to tumour doubling revealed that the combination of MGI 114 and TPT at 2.5 and 0.5 mg/kg, respectively, was synergistic. These results suggest that cytotoxic activity is enhanced when MGI 114 is combined with either TPT or paclitaxel, and clinical trials to further evaluate these combination regimens are warranted. (C) 2000 Elsevier Science Ltd.

Original languageEnglish (US)
Pages (from-to)2430-2436
Number of pages7
JournalEuropean Journal of Cancer
Volume36
Issue number18
DOIs
StatePublished - 2000

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Topotecan
Paclitaxel
Heterografts
Carcinoma
Lung
irofulven
Tumor Burden
Lung Neoplasms
Agaricales

Keywords

  • 6-Hydroxymethylacylfulvene (MGI 114
  • Illudins
  • Irofulven)
  • Lung cancer
  • Paclitaxel
  • Topotecan

ASJC Scopus subject areas

  • Cancer Research
  • Hematology
  • Oncology

Cite this

Enhanced antitumour activity of 6-hydroxymethylacylfulvene in combination with topotecan or paclitaxel in the MV522 lung carcinoma xenograft model. / Hammond, L. A.; Hilsenbeck, S. G.; Eckhardt, S. G.; Marty, J.; Mangold, G.; MacDonald, J. R.; Rowinsky, E. K.; Von Hoff, D. D.; Weitman, Steven D.

In: European Journal of Cancer, Vol. 36, No. 18, 2000, p. 2430-2436.

Research output: Contribution to journalArticle

Hammond, LA, Hilsenbeck, SG, Eckhardt, SG, Marty, J, Mangold, G, MacDonald, JR, Rowinsky, EK, Von Hoff, DD & Weitman, SD 2000, 'Enhanced antitumour activity of 6-hydroxymethylacylfulvene in combination with topotecan or paclitaxel in the MV522 lung carcinoma xenograft model', European Journal of Cancer, vol. 36, no. 18, pp. 2430-2436. https://doi.org/10.1016/S0959-8049(00)00302-6
Hammond, L. A. ; Hilsenbeck, S. G. ; Eckhardt, S. G. ; Marty, J. ; Mangold, G. ; MacDonald, J. R. ; Rowinsky, E. K. ; Von Hoff, D. D. ; Weitman, Steven D. / Enhanced antitumour activity of 6-hydroxymethylacylfulvene in combination with topotecan or paclitaxel in the MV522 lung carcinoma xenograft model. In: European Journal of Cancer. 2000 ; Vol. 36, No. 18. pp. 2430-2436.
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abstract = "6-Hydroxymethylacylfulvene (HMAF; MGI 114; Irofulven) is a semisynthetic analogue of the toxin illudin S, which is a product of the Omphalotus mushroom. MGI 114 induces cytotoxicity against a broad range of solid tumours in vivo, including the drug-refractory MV522 human lung cancer xenograft. In this study, the potential application of MGI 114 in the treatment of lung cancer was explored by evaluating the activity of MGI 114 in combination with either topotecan (TPT) or paclitaxel. Groups of eight nude mice bearing MV522 xenografts were treated with MGI 114, TPT or paclitaxel as single agents and with MGI 114 in combination with TPT or paclitaxel. MGI 114 was administered at doses of 2.5 and 5.0 mg/kg intraperitoneally (i.p.) daily on days 1-5, while TPT and paclitaxel were administered at doses of 0.5 or 1.0 mg/kg and 20 mg/kg, respectively, i.p. on days 1-5. In the single-agent studies, MGI 114, TPT and paclitaxel all resulted in decreased final tumour weights compared with vehicle-treated controls. As single agents, TPT, at the 0.5 mg/kg dose level, and paclitaxel, at the 20 mg/kg dose level, produced partial shrinkages (PSs). All combinations of MGI 114, and either TPT or paclitaxel, produced decrements in final tumour weights compared with monotherapy with the same doses of MGI 114, TPT and paclitaxel. Although all animals treated with the combination of MGI 114 and paclitaxel experienced PSs or complete shrinkages (CSs) (or died), analysis of the time to tumour doubling revealed that the combination of MGI 114 and TPT at 2.5 and 0.5 mg/kg, respectively, was synergistic. These results suggest that cytotoxic activity is enhanced when MGI 114 is combined with either TPT or paclitaxel, and clinical trials to further evaluate these combination regimens are warranted. (C) 2000 Elsevier Science Ltd.",
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AU - Hammond, L. A.

AU - Hilsenbeck, S. G.

AU - Eckhardt, S. G.

AU - Marty, J.

AU - Mangold, G.

AU - MacDonald, J. R.

AU - Rowinsky, E. K.

AU - Von Hoff, D. D.

AU - Weitman, Steven D

PY - 2000

Y1 - 2000

N2 - 6-Hydroxymethylacylfulvene (HMAF; MGI 114; Irofulven) is a semisynthetic analogue of the toxin illudin S, which is a product of the Omphalotus mushroom. MGI 114 induces cytotoxicity against a broad range of solid tumours in vivo, including the drug-refractory MV522 human lung cancer xenograft. In this study, the potential application of MGI 114 in the treatment of lung cancer was explored by evaluating the activity of MGI 114 in combination with either topotecan (TPT) or paclitaxel. Groups of eight nude mice bearing MV522 xenografts were treated with MGI 114, TPT or paclitaxel as single agents and with MGI 114 in combination with TPT or paclitaxel. MGI 114 was administered at doses of 2.5 and 5.0 mg/kg intraperitoneally (i.p.) daily on days 1-5, while TPT and paclitaxel were administered at doses of 0.5 or 1.0 mg/kg and 20 mg/kg, respectively, i.p. on days 1-5. In the single-agent studies, MGI 114, TPT and paclitaxel all resulted in decreased final tumour weights compared with vehicle-treated controls. As single agents, TPT, at the 0.5 mg/kg dose level, and paclitaxel, at the 20 mg/kg dose level, produced partial shrinkages (PSs). All combinations of MGI 114, and either TPT or paclitaxel, produced decrements in final tumour weights compared with monotherapy with the same doses of MGI 114, TPT and paclitaxel. Although all animals treated with the combination of MGI 114 and paclitaxel experienced PSs or complete shrinkages (CSs) (or died), analysis of the time to tumour doubling revealed that the combination of MGI 114 and TPT at 2.5 and 0.5 mg/kg, respectively, was synergistic. These results suggest that cytotoxic activity is enhanced when MGI 114 is combined with either TPT or paclitaxel, and clinical trials to further evaluate these combination regimens are warranted. (C) 2000 Elsevier Science Ltd.

AB - 6-Hydroxymethylacylfulvene (HMAF; MGI 114; Irofulven) is a semisynthetic analogue of the toxin illudin S, which is a product of the Omphalotus mushroom. MGI 114 induces cytotoxicity against a broad range of solid tumours in vivo, including the drug-refractory MV522 human lung cancer xenograft. In this study, the potential application of MGI 114 in the treatment of lung cancer was explored by evaluating the activity of MGI 114 in combination with either topotecan (TPT) or paclitaxel. Groups of eight nude mice bearing MV522 xenografts were treated with MGI 114, TPT or paclitaxel as single agents and with MGI 114 in combination with TPT or paclitaxel. MGI 114 was administered at doses of 2.5 and 5.0 mg/kg intraperitoneally (i.p.) daily on days 1-5, while TPT and paclitaxel were administered at doses of 0.5 or 1.0 mg/kg and 20 mg/kg, respectively, i.p. on days 1-5. In the single-agent studies, MGI 114, TPT and paclitaxel all resulted in decreased final tumour weights compared with vehicle-treated controls. As single agents, TPT, at the 0.5 mg/kg dose level, and paclitaxel, at the 20 mg/kg dose level, produced partial shrinkages (PSs). All combinations of MGI 114, and either TPT or paclitaxel, produced decrements in final tumour weights compared with monotherapy with the same doses of MGI 114, TPT and paclitaxel. Although all animals treated with the combination of MGI 114 and paclitaxel experienced PSs or complete shrinkages (CSs) (or died), analysis of the time to tumour doubling revealed that the combination of MGI 114 and TPT at 2.5 and 0.5 mg/kg, respectively, was synergistic. These results suggest that cytotoxic activity is enhanced when MGI 114 is combined with either TPT or paclitaxel, and clinical trials to further evaluate these combination regimens are warranted. (C) 2000 Elsevier Science Ltd.

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