title: Correlation of MRI biomarkers with tumor necrosis in Hras5 tumor xenograft in athymic rats.
abstract: Magnetic resonance imaging (MRI) can measure the effects of therapies targeting the tumor vasculature and has demonstrated that vascular-damaging agents (VDA) induce acute vascular shutdown in tumors in human and animal models. However, at subtherapeutic doses, blood flow may recover before the induction of significant levels of necrosis. We present the relationship between changes in MRI biomarkers and tumor necrosis. Multiple MRI measurements were taken at 4.7 T in athymic rats (n = 24) bearing 1.94 +/- 0.2-cm3 subcutaneous Hras5 tumors (ATCC 41000) before and 24 hours after clinically relevant doses of the VDA, ZD6126 (0-10 mg/kg, i.v.). We measured effective transverse relaxation rate (R2*), initial area under the gadolinium concentration-time curve (IAUGC(60/150)), equivalent enhancing fractions (EHF(60/150)), time constant (K(trans)), proportion of hypoperfused voxels as estimated from fit failures in K(trans) analysis, and signal intensity (SI) in T2-weighted MRI (T(2)W). ZD6126 treatment induced > 90% dose-dependent tumor necrosis at 10 mg/kg; correspondingly, SI changes were evident from T2W MRI. Although R2* did not correlate, other MRI biomarkers significantly correlated with necrosis at doses of > or = 5 mg/kg ZD6126. These data on Hras5 tumors suggest that the quantification of hypoperfused voxels might provide a useful biomarker of tumor necrosis.
authors.affiliation: Discovery Enabling Capabilities and Sciences, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK. daniel.bradley@astrazeneca.com
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Bradley
authors.forename: Jean J
authors.initials: JJ
authors.lastname: Tessier
authors.forename: Susan E
authors.initials: SE
authors.lastname: Ashton
authors.forename: John C
authors.initials: JC
authors.lastname: Waterton
authors.forename: Zena
authors.initials: Z
authors.lastname: Wilson
authors.forename: Philip L
authors.initials: PL
authors.lastname: Worthington
authors.forename: Anderson J
authors.initials: AJ
authors.lastname: Ryan
mesh_terms: D000818:Animals; D015415:Biomarkers; D004305:Dose-Response Relationship, Drug; D011905:Genes, ras; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D041681:NIH 3T3 Cells; D009336:Necrosis; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D009943:Organophosphorus Compounds / Q000627:therapeutic use*; D051381:Rats; D011923:Rats, Nude; D014183:Transplantation, Heterologous
chemical_list: D015415:Biomarkers; C455219:N-acetylcochinol-O-phosphate; D009943:Organophosphorus Compounds