title: Intra-arterial administration improves temozolomide delivery and efficacy in a model of intracerebral metastasis, but has unexpected brain toxicity.
abstract: We tested the hypothesis that intra-arterial (IA) infusion of temozolomide into the internal carotid artery would safely improve drug delivery to brain and enhance chemotherapy efficacy in a chemosensitive rat brain tumor model. Quantitative autoradiography after 25 µCi (14)C-temozolomide was given by oral, intravenous, or IA route of administration, or IA with osmotic blood-brain barrier disruption (BBBD) (n = 5-7 per group) showed that both IA and IA/BBBD administration increased drug delivery in tumor by over threefold compared to normal brain (P < 0.02), and also significantly elevated delivery throughout the infused right hemisphere. Temozolomide (20 mg/kg; ~150 mg/m(2)) increased median survival when given by oral (25.5 days), intravenous (25.5 days), or IA (33 days) route of administration, compared to 17.5 days in untreated controls (n = 8 per group; overall P < 0.0001). Survival time after IA temozolomide was significantly longer than all other groups (P < 0.01 for all comparisons). BBBD temozolomide was toxic in the efficacy study, but there was no evidence of symptomatic neurotoxicity in rats given IA temozolomide. After these promising animal results, a 49 year old male with glioblastoma multiforme who failed all standard therapy received temozolomide 100 mg/m(2) IA. Upon initiation of the second course of IA infusion the patient had increased heart rate, blood pressure, and rash, and the procedure was terminated without sequelae. Follow up IA infusion of temozolomide diluent in normal rats showed damaged cerebrovasculature as determined by dye leakage. These results demonstrate that IA infusion of temozolomide was toxic, with or without BBBD. We conclude that under the current formulation temozolomide is not safe for IA infusion in patients.
authors.affiliation: Department of Neurology, Oregon Health & Sciences University, L603; 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA.|Department of Cell, Developmental and Cancer Biology, Oregon Health & Sciences University, Portland, OR, 97239, USA.
authors.forename: Leslie L
authors.initials: LL
authors.lastname: Muldoon
authors.affiliation: Veterans Administration Medical Center, Portland, OR, 97239, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Pagel
authors.affiliation: Department of Neurology, Oregon Health & Sciences University, L603; 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA.
authors.forename: Joao Prola
authors.initials: JP
authors.lastname: Netto
authors.affiliation: Department of Neurology, Oregon Health & Sciences University, L603; 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA. neuwelte@ohsu.edu.|Department of Neurosurgery, Oregon Health & Sciences University, Portland, OR, 97239, USA. neuwelte@ohsu.edu.|Veterans Administration Medical Center, Portland, OR, 97239, USA. neuwelte@ohsu.edu.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Neuwelt
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000009:adverse effects; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000556:secondary; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D016503:Drug Delivery Systems; D006801:Humans; D007269:Injections, Intra-Arterial; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000473:pathology; D051381:Rats; D011923:Rats, Nude; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000473:pathology; D000077204:Temozolomide; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D000077204:Temozolomide
keywords: Animal model; Case study; Chemotherapy; Intra-arterial infusion