title: Diffusion-weighted MRI for imaging cell death after cytotoxic or apoptosis-inducing therapy.
abstract: BACKGROUND
  Non-invasive serial imaging is desirable to detect processes such as necrotic and apoptotic cell death in cancer patients undergoing treatment. This study investigated the use of diffusion-weighted (DW-) magnetic resonance imaging (MRI) for imaging cell death induced by either a cytotoxic drug (irinotecan), or the apoptosis-inducing agent birinapant, in human tumour xenografts in vivo.
  
  
  METHODS
  Nude mice bearing human SW620 colon carcinoma xenografts were treated with vehicle, irinotecan (50 mg kg(-1)) or birinapant (30 mg kg(-1)) for up to 5 days. DW-MRI was performed prior to and on days 1, 3 and 5 during treatment. Assessment of tumour apoptosis and necrosis ex vivo was used to validate the imaging findings.
  
  
  RESULTS
  Both irinotecan and birinapant induced significant tumour growth delay. Irinotecan induced a small increase in the tumour apparent diffusion coefficient (ADC) after 1 day, with a 20 and 30% increase at days 3 and 5 respectively. ADC was unchanged in the vehicle- and birinapant-treated tumours despite a growth delay in the latter. Histological analysis showed that irinotecan increased necrosis at days 3 and 5, and induced apoptosis after 1 day, compared with vehicle. Birinapant induced apoptosis after day 3, but had no effect on tumour necrosis.
  
  
  CONCLUSIONS
  Tumour ADC changes after irinotecan treatment were associated with the induction of a mixture of necrotic and apoptotic cell death, whereas induction of apoptosis alone with birinapant was not sufficient to induce changes in tissue microstructure that were detectable with DW-MRI. ADC is a useful non-invasive biomarker for early detection of response to cytotoxic drugs, but false negatives may arise while detecting apoptotic response to birinapant.
authors.affiliation: Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, 15 Cotswold Road, Belmont, Sutton, Surrey SM2 5NG, UK.
authors.forename: E
authors.initials: E
authors.lastname: Papaevangelou
authors.affiliation: Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, 15 Cotswold Road, Belmont, Sutton, Surrey SM2 5NG, UK.
authors.forename: G S
authors.initials: GS
authors.lastname: Almeida
authors.affiliation: Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, 15 Cotswold Road, Belmont, Sutton, Surrey SM2 5NG, UK.
authors.forename: Y
authors.initials: Y
authors.lastname: Jamin
authors.affiliation: Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, 15 Cotswold Road, Belmont, Sutton, Surrey SM2 5NG, UK.
authors.forename: S P
authors.initials: SP
authors.lastname: Robinson
authors.affiliation: Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, 15 Cotswold Road, Belmont, Sutton, Surrey SM2 5NG, UK.
authors.forename: N M
authors.initials: NM
authors.lastname: deSouza
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D038524:Diffusion Magnetic Resonance Imaging / Q000379:methods*; D004151:Dipeptides / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D007211:Indoles / Q000494:pharmacology*; D000077146:Irinotecan; D008207:Lymphatic Metastasis; D051379:Mice; D008819:Mice, Nude; D009336:Necrosis; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004151:Dipeptides; D007211:Indoles; C582429:birinapant; D000077146:Irinotecan; D002166:Camptothecin