title: Quantified tumor t1 is a generic early-response imaging biomarker for chemotherapy reflecting cell viability.
abstract: OBJECTIVE
  Identification of a generic response biomarker by comparison of chemotherapeutics with different action mechanisms on several noninvasive biomarkers in experimental tumor models.
  
  
  METHODS
  The spin-lattice relaxation time of water protons (T(1)) was quantified using an inversion recovery-TrueFISP magnetic resonance imaging method in eight different experimental tumor models before and after treatment at several different time points with five different chemotherapeutics. Effects on T(1) were compared with other minimally invasive biomarkers including vascular parameters, apparent diffusion coefficient, and interstitial fluid pressure, and were correlated with efficacy at the endpoint and histologic parameters.
  
  
  RESULTS
  In all cases, successful chemotherapy significantly lowered tumor T(1) compared with vehicle and the fractional change in T(1) (DeltaT(1)) correlated with the eventual change in tumor size (range: r(2) = 0.21, P < 0.05 to r(2) = 0.73, P < 0.0001), except for models specifically resistant to that drug. In RIF-1 tumors, interstitial fluid pressure was decreased, but apparent diffusion coefficient and permeability increased in response to the microtubule stabilizer patupilone and 5-fluorouracil. Although DeltaT(1) was small (maximum of -20%), the variability was very low (5%) compared with other magnetic resonance imaging methods (24-48%). Analyses ex vivo showed unchanged necrosis, increased apoptosis, and decreased %Ki67 and total choline, but only Ki67 and choline correlated with DeltaT(1). Correlation of Ki67 and DeltaT(1) were observed in other models using patupilone, paclitaxel, a VEGF-R inhibitor, and the mammalian target of rapamycin inhibitor everolimus.
  
  
  CONCLUSIONS
  These results suggest that a decrease in tumor T(1) reflects hypocellularity and is a generic marker of response. The speed and robustness of the method should facilitate its use in clinical trials.
authors.affiliation: Oncology Research and Global Imaging Group, Novartis Institutes for Biomedical Research, Basel, Switzerland. paul_mj.mcsheehy@novartis.com
authors.forename: Paul M J
authors.initials: PM
authors.lastname: McSheehy
authors.forename: Claudia
authors.initials: C
authors.lastname: Weidensteiner
authors.forename: Catherine
authors.initials: C
authors.lastname: Cannet
authors.forename: Stephane
authors.initials: S
authors.lastname: Ferretti
authors.forename: Didier
authors.initials: D
authors.lastname: Laurent
authors.forename: Stephan
authors.initials: S
authors.lastname: Ruetz
authors.forename: Michael
authors.initials: M
authors.lastname: Stumm
authors.forename: Peter R
authors.initials: PR
authors.lastname: Allegrini
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015415:Biomarkers; D045744:Cell Line, Tumor; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology*; D051381:Rats; D011914:Rats, Inbred BN
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers