title: Acute tumor response to ZD6126 assessed by intrinsic susceptibility magnetic resonance imaging.
abstract: The effective magnetic resonance imaging (MRI) transverse relaxation rate R(2)* was investigated as an early acute marker of the response of rat GH3 prolactinomas to the vascular-targeting agent, ZD6126. Multigradient echo (MGRE) MRI was used to quantify R(2)*, which is sensitive to tissue deoxyhemoglobin levels. Tumor R(2)* was measured prior to, and either immediately for up to 35 minutes, or 24 hours following administration of 50 mg/kg ZD6126. Following MRI, tumor perfusion was assessed by Hoechst 33342 uptake. Tumor R(2)* significantly increased to 116 +/- 4% of baseline 35 minutes after challenge, consistent with an ischemic insult induced by vascular collapse. A strong positive correlation between baseline R(2)* and the subsequent increase in R(2)* measured 35 minutes after treatment was obtained, suggesting that the baseline R(2)* is prognostic for the subsequent tumor response to ZD6126. In contrast, a significant decrease in tumor R(2)* was found 24 hours after administration of ZD6126. Both the 35-minute and 24-hour R(2)* responses to ZD6126 were associated with a decrease in Hoechst 33342 uptake. Interpretation of the R(2)* response is complex, yet changes in tumor R(2)* may provide a convenient and early MRI biomarker for detecting the antitumor activity of vascular-targeting agents.
authors.affiliation: Department of Basic Medical Sciences, St. George's Hospital Medical School, London SW17 ORE, UK. s.robinson@sghms.ac.uk
authors.forename: Simon P
authors.initials: SP
authors.lastname: Robinson
authors.forename: Tammy L
authors.initials: TL
authors.lastname: Kalber
authors.forename: Franklyn A
authors.initials: FA
authors.lastname: Howe
authors.forename: Dominick J O
authors.initials: DJ
authors.lastname: McIntyre
authors.forename: John R
authors.initials: JR
authors.lastname: Griffiths
authors.forename: David C
authors.initials: DC
authors.lastname: Blakey
authors.forename: Lynsey
authors.initials: L
authors.lastname: Whittaker
authors.forename: Anderson J
authors.initials: AJ
authors.lastname: Ryan
authors.forename: John C
authors.initials: JC
authors.lastname: Waterton
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology; D005260:Female; D006454:Hemoglobins / Q000737:chemistry; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008856:Microscopy, Fluorescence; D009369:Neoplasms / Q000175:diagnosis* / Q000188:drug therapy*; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D010477:Perfusion; D011379:Prognosis; D015175:Prolactinoma / Q000188:drug therapy; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D006454:Hemoglobins; C455219:N-acetylcochinol-O-phosphate; D009943:Organophosphorus Compounds; C100003:deoxyhemoglobin; C017807:bisbenzimide ethoxide trihydrochloride