title: Therapeutic efficacy of DTI-015 using diffusion magnetic resonance imaging as an early surrogate marker.
abstract: To investigate diffusion weighted magnetic resonance imaging as a quantitative surrogate marker for evaluating the therapy-induced cellular changes in an orthotopic experimental glioma model, tumors were treated with direct intratumoral administration of DTI-015, a solution of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in 100% EtOH. Intracerebral 9L tumors were induced in Fischer 344 rats, and three treatment groups were established: DTI-015, EtOH, and sham. Two groups of rats received intratumoral injection of either 67 mg/mL BCNU in EtOH or EtOH alone at 50% of the tumor volume up to a maximum of 30 mul under stereotactic guidance. Diffusion magnetic resonance images were acquired before treatment and after treatment at 1, 24, 48, and 72 hours and then 3 times per week thereafter. Tumor cell viability was examined using multislice diffusion weighted magnetic resonance imaging with diffusion weighted transverse magnetic resonance images and histogram plots of each tumor quantified over time. Control animals (EtOH- or sham-treated animals) showed mean apparent diffusion coefficients (ADCs) that remained essentially unchanged over the experimental time course. In contrast, rats treated with DTI-015 showed a significant increase in ADC relative to the pretreatment within 24 hours, which further increased over time, followed by a significant therapeutic response as evidenced by subsequent tumor volume shrinkage, development of a cystic region, and enhanced animal survival. Finally, not only were ADC measurements predictive of differences between treatment groups, but they also yielded spatial and temporal data regarding the efficacy of treatment within individual treated animals that could be used to guide subsequent therapy.
authors.affiliation: University of Michigan, Center for Molecular Imaging and Department of Radiology, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0648, USA.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Hall
authors.forename: Bradford A
authors.initials: BA
authors.lastname: Moffat
authors.forename: Jadranka
authors.initials: J
authors.lastname: Stojanovska
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Johnson
authors.forename: Zhuolin
authors.initials: Z
authors.lastname: Li
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Hamstra
authors.forename: Alnawaz
authors.initials: A
authors.lastname: Rehemtulla
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Chenevert
authors.forename: Julie
authors.initials: J
authors.lastname: Carter
authors.forename: Dennis
authors.initials: D
authors.lastname: Pietronigro
authors.forename: Brian D
authors.initials: BD
authors.lastname: Ross
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002330:Carmustine / Q000627:therapeutic use*; D038524:Diffusion Magnetic Resonance Imaging; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D015996:Survival Rate; D014407:Tumor Cells, Cultured
chemical_list: D018906:Antineoplastic Agents, Alkylating; D014408:Biomarkers, Tumor; D002330:Carmustine