title: Systemic rapamycin alone may not be a treatment option for malignant glioma: evidence from an in vivo study.
abstract: The mammalian target of rapamycin (mTOR) plays a central role in regulating the proliferation of cancer cells, and mTOR-specific inhibitors such as rapamycin analogs are considered as a promising therapy for malignant glioma. In this study, we investigated the possibility of using mTOR inhibitors to treat gliomas. We used a molecular marker, phosphorylation of S6 protein, to monitor biological effects of mTOR inhibitors within xenografts. Phosphorylation was decreased more in U87MG glioma after treatment with high doses of rapamycin or its analog, torisel (10 mg/kg or 25 mg/kg), but only slightly after a low dose of rapamycin (3 mg/kg). This effect correlated with enhanced survival of rats after weekly peritoneal injections of both drugs at the highest two doses but not at the low dose. High doses of both drugs caused weight loss in rats. Clinical trial data indicates that low doses of Torisel (<3 mg/kg) were not efficacious in recurrent GBM. It is concluded that systemic administration of rapamycin analogues may not be a treatment option for patients with malignant glioma due to the intolerability of high doses that might otherwise be effective. The present study underscores the need for better pre-clinical evaluation of drugs with respect to therapeutic window.
authors.affiliation: Department of Neurosurgery, University of California San Francisco, San Francisco, CA 94103, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Mendiburu-Eliçabe
authors.forename: Dali
authors.initials: D
authors.lastname: Yin
authors.forename: Piotr
authors.initials: P
authors.lastname: Hadaczek
authors.forename: Yuying
authors.initials: Y
authors.lastname: Zhai
authors.forename: John
authors.initials: J
authors.lastname: Forsayeth
authors.forename: Krystof S
authors.initials: KS
authors.lastname: Bankiewicz
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D008297:Male; D009368:Neoplasm Transplantation; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D011923:Rats, Nude; D020123:Sirolimus / Q000008:administration & dosage*; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: D007166:Immunosuppressive Agents; D011494:Protein Kinases; D020123:Sirolimus