title: Amino acid PET tracers are reliable markers of treatment responses to single-agent or combination therapies including temozolomide, interferon-β, and/or bevacizumab for glioblastoma.
abstract: BACKGROUND
  We examined whether the amino acid PET tracers, trans-1-amino-3-(18)F-fluorocyclobutanecarboxylic acid (anti-(18)F-FACBC) and (11)C-methyl-l-methionine ((11)C-Met), are suitable for detecting early responses to combination therapies including temozolomide (TMZ), interferon-β (IFN), and bevacizumab (Bev) in glioblastoma.
  
  
  METHODS
  Human glioblastoma U87MG (U87) cells were incubated with low dose TMZ to induce chemoresistance. Both trans-1-amino-3-fluoro-1-(14)C-cyclobutanecarboxylic acid (anti-(14)C-FACBC) and (3)H-methyl-l-methionine ((3)H-Met) uptake were quantified using triple-label accumulation assays to examine the relationship between tracer uptake and proliferation ((3)H-thymidine (TdR) accumulation) in vitro. U87 and U87R (TMZ-resistant subculture) cells were inoculated into the right and left basal ganglia, respectively, of F344/N-rnu rats. The efficacy of single-agent (TMZ, Bev) and combination therapy (TMZ/IFN, TMZ/Bev, TMZ/IFN/Bev) was examined in orthotopic gliomas using MRI, Evans blue extravasation, anti-(14)C-FACBC, and (3)H-Met autoradiography, and MIB-1 immunostaining.
  
  
  RESULTS
  TMZ treatment decreased (3)H-TdR accumulation and the volume distribution of anti-(14)C-FACBC and (3)H-Met in U87 but not U87R cells. TMZ/IFN combination therapy significantly decreased these parameters in U87R cells; however, Bev had no additional effect in vitro. In vivo, U87R-derived gliomas were observed as equivocal tumors on MRI and T2-high intensity lesions. Bev treatment, either alone or in combination, markedly decreased U87 enhancing lesions. By contrast, autoradiographic images using anti-(14)C-FACBC and (3)H-Met clearly delineated tumor extent, which spread widely beyond T2-high intensity lesions and enhancing lesions. TMZ therapy significantly decreased tracer accumulation and proliferation of U87- but not U87R-derived tumors. TMZ/IFN combination treatment significantly decreased these parameters in U87R tumors, which were further reduced (in both tumor types) by Bev addition. Tracer uptake correlated with the MIB-1 proliferation index. However, MRI was unsuitable for tumor delineation and assessment of Bev treatment response.
  
  
  CONCLUSIONS
  Triple-agent therapy (TMZ/IFN/Bev) was effective against even TMZ-resistant glioblastomas. PET with amino acid tracers provides useful information on the early response of glioblastomas to single-agent and combination therapy.
authors.affiliation: Department of Neurosurgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ono
authors.affiliation: Department of Neurosurgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan. Electronic address: sasajima@nsg.med.akita-u.ac.jp.
authors.forename: Toshio
authors.initials: T
authors.lastname: Sasajima
authors.affiliation: Research Center, Nihon Medi-Physics Co., Ltd., 3-1 Sodegaura, Chiba 299-0266, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Doi
authors.affiliation: Research Center, Nihon Medi-Physics Co., Ltd., 3-1 Sodegaura, Chiba 299-0266, Japan.
authors.forename: Shuntaro
authors.initials: S
authors.lastname: Oka
authors.affiliation: Research Center, Nihon Medi-Physics Co., Ltd., 3-1 Sodegaura, Chiba 299-0266, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ono
authors.affiliation: Research Center, Nihon Medi-Physics Co., Ltd., 3-1 Sodegaura, Chiba 299-0266, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Kanagawa
authors.affiliation: Research Center, Nihon Medi-Physics Co., Ltd., 3-1 Sodegaura, Chiba 299-0266, Japan.
authors.forename: Atsumi
authors.initials: A
authors.lastname: Baden
authors.affiliation: Department of Neurosurgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Mizoi
authors.affiliation: Department of Neurosurgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimizu
mesh_terms: D000596:Amino Acids / Q000493:pharmacokinetics*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D000068258:Bevacizumab / Q000008:administration & dosage; D014408:Biomarkers, Tumor / Q000378:metabolism; D001932:Brain Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005909:Glioblastoma / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D016899:Interferon-beta / Q000008:administration & dosage; D008297:Male; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D011916:Rats, Inbred F344; D011923:Rats, Nude; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D000077204:Temozolomide; D014018:Tissue Distribution; D016896:Treatment Outcome
chemical_list: D000596:Amino Acids; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D019275:Radiopharmaceuticals; D000068258:Bevacizumab; D016899:Interferon-beta; D003606:Dacarbazine; D000077204:Temozolomide
keywords: Anti-FACBC; Bevacizumab; Glioblastoma; Interferon-β; Temozolomide