title: Local delivery of rapamycin: a toxicity and efficacy study in an experimental malignant glioma model in rats.
abstract: Rapamycin, an anti-proliferative agent, is effective in the treatment of renal cell carcinoma and recurrent breast cancers. We proposed that this potent mammalian target of rapamycin inhibitor may be useful for the treatment of gliomas as well. We examined the cytotoxicity of rapamycin against a rodent glioma cell line, determined the toxicity of rapamycin when delivered intracranially, and investigated the efficacy of local delivery of rapamycin for the treatment of experimental malignant glioma in vivo. We also examined the dose-dependent efficacy of rapamycin and the effect when locally delivered rapamycin was combined with radiation therapy. Rapamycin was cytotoxic to 9L cells, causing 34% growth inhibition at a concentration of 0.01 µg/mL. No in vivo toxicity was observed when rapamycin was incorporated into biodegradable caprolactone-glycolide (35:65) polymer beads at 0.3%, 3%, and 30% loading doses and implanted intracranially. Three separate efficacy studies were performed to test the reproducibility of the effect of the rapamycin beads as well as the validity of this treatment approach. Animals treated with the highest dose of rapamycin beads tested (30%) consistently demonstrated significantly longer survival durations than the control and placebo groups. All dose-escalating rapamycin bead treatment groups (0.3%, 3% and 30%), treated both concurrently with tumor and in a delayed manner after tumor placement, experienced a significant increase in survival, compared with controls. Radiation therapy in addition to the simultaneous treatment with 30% rapamycin beads led to significantly longer survival duration than either therapy alone. These results suggest that the local delivery of rapamycin for the treatment of gliomas should be further investigated.
authors: Department of Neurosurgery, Johns Hopkins Hospital, Baltimore, MD, USA. btyler@jhmi.edu
authors: Betty
authors: B
authors: Tyler
authors: Scott
authors: S
authors: Wadsworth
authors: Violette
authors: V
authors: Recinos
authors: Vivek
authors: V
authors: Mehta
authors: Ananth
authors: A
authors: Vellimana
authors: Khan
authors: K
authors: Li
authors: Joel
authors: J
authors: Rosenblatt
authors: Hiep
authors: H
authors: Do
authors: Gary L
authors: GL
authors: Gallia
authors: I-Mei
authors: IM
authors: Siu
authors: Robert T
authors: RT
authors: Wicks
authors: Michelle A
authors: MA
authors: Rudek
authors: Ming
authors: M
authors: Zhao
authors: Henry
authors: H
authors: Brem
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects* / Q000528:radiation effects; D003131:Combined Modality Therapy; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D006801:Humans; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D011108:Polymers / Q000737:chemistry; D011878:Radiotherapy; D051381:Rats; D011916:Rats, Inbred F344; D020123:Sirolimus / Q000627:therapeutic use*; D015996:Survival Rate
chemical_list: D000903:Antibiotics, Antineoplastic; D011108:Polymers; D020123:Sirolimus