Inhibition of the mammalian target of rapamycin sensitizes U87 xenografts to fractionated radiation therapy

Jeffrey S. Eshleman, Brett L. Carlson, Ann C. Mladek, Brian D. Kastner, Kathleen L. Shide, Jann N Sarkaria

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Abstract

The mammalian target of rapamycin (mTOR) modulates key signaling pathways that promote uncontrolled proliferation of glioblastoma multiforme (GBM). Because rapid tumor proliferation may contribute to the clinical radioresistance of GBM tumors, the combination of rapamycin, a selective mTOR inhibitor, and radiation was studied in vitro and in vivo in a GBM model. In monolayer cultures of U87 and SKMG-3 cells, rapamycin had no impact on radiation sensitivity. In contrast, rapamycin significantly enhanced the efficacy of fractionated radiation of established U87 xenografts in nude mice. Similar effects were seen in U87 spheroids treated with rapamycin and radiation, which suggests that the sensitizing effects of this drug are dependent on disruption of mTOR signaling pathways specifically within tumor cells. Inhibition of these signaling pathways can lead to inhibition of G1-specific cyclin-dependent kinase activities, and this could contribute to the sensitizing effects of rapamycin. Consistent with this idea, roscovitine, a specific cyclin-dependent kinase inhibitor, also enhanced the efficacy of fractionated radiation in U87 spheroids. These data demonstrate that inhibition of tumor proliferation does not diminish the efficacy of fractionated radiation and suggest that disruption of key signal transduction pathways may significantly enhance the effectiveness of radiation therapy in malignant gliomas.

Original languageEnglish (US)
Pages (from-to)7291-7297
Number of pages7
JournalCancer Research
Volume62
Issue number24
StatePublished - Dec 15 2002

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Sirolimus
Heterografts
Radiotherapy
Radiation
Glioblastoma
Cyclin-Dependent Kinases
Neoplasms
Radiation Tolerance
Nude Mice
Glioma
Signal Transduction
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Eshleman, J. S., Carlson, B. L., Mladek, A. C., Kastner, B. D., Shide, K. L., & Sarkaria, J. N. (2002). Inhibition of the mammalian target of rapamycin sensitizes U87 xenografts to fractionated radiation therapy. Cancer Research, 62(24), 7291-7297.

Inhibition of the mammalian target of rapamycin sensitizes U87 xenografts to fractionated radiation therapy. / Eshleman, Jeffrey S.; Carlson, Brett L.; Mladek, Ann C.; Kastner, Brian D.; Shide, Kathleen L.; Sarkaria, Jann N.

In: Cancer Research, Vol. 62, No. 24, 15.12.2002, p. 7291-7297.

Research output: Contribution to journalArticle

Eshleman, JS, Carlson, BL, Mladek, AC, Kastner, BD, Shide, KL & Sarkaria, JN 2002, 'Inhibition of the mammalian target of rapamycin sensitizes U87 xenografts to fractionated radiation therapy', Cancer Research, vol. 62, no. 24, pp. 7291-7297.
Eshleman JS, Carlson BL, Mladek AC, Kastner BD, Shide KL, Sarkaria JN. Inhibition of the mammalian target of rapamycin sensitizes U87 xenografts to fractionated radiation therapy. Cancer Research. 2002 Dec 15;62(24):7291-7297.
Eshleman, Jeffrey S. ; Carlson, Brett L. ; Mladek, Ann C. ; Kastner, Brian D. ; Shide, Kathleen L. ; Sarkaria, Jann N. / Inhibition of the mammalian target of rapamycin sensitizes U87 xenografts to fractionated radiation therapy. In: Cancer Research. 2002 ; Vol. 62, No. 24. pp. 7291-7297.
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