title: Prognostic and predictive role of lactate dehydrogenase 5 expression in colorectal cancer patients treated with PTK787/ZK 222584 (vatalanib) antiangiogenic therapy.
abstract: OBJECTIVE
  The Colorectal Oral Novel therapy For the Inhibition of angiogenesis and Retarding of Metastases (CONFIRM)-randomized trials, investigating the role of the VEGF-receptor inhibitor PTK787/ZK 222584 (vatalanib) in colorectal cancer (FOLFOX 4 ± vatalanib), showed some benefit in patients with high serum lactate dehydrogenase (LDH) levels. Here, we investigated the expression of LDH5 (encoded entirely by the LDHA gene, regulated by the hypoxia inducible factors) in cancer tissues from patients recruited in the CONFIRM trials and relationship to response.
  
  
  METHODS
  Paraffin-embedded materials from 179 patients recruited in the CONFIRM trials were analyzed by immunohistochemistry for the expression of the LDH5 protein. Correlations with serum LDH, response, and survival were assessed.
  
  
  RESULTS
  A significant association of tumor burden and of poor performance status (PS) with serum LDH was noted. Poor PS and high tumor LDH5 expression predicted for poor response rates. High tissue LDH5 was related to poor progression-free survival (PFS) only in the placebo group of patients, whereas the addition of vatalanib seemed to improved response and PFS in this subgroup. High serum LDH levels were linked with significantly poorer overall survival, which however was not sustained in multivariate analysis.
  
  
  CONCLUSIONS
  Serum LDH and tissue LDH5 levels are complementary features that help to characterize the activity of LDH in colorectal cancer and have a potent value in predicting response to chemotherapy. The addition of vatalanib diminished the impact of LDH expression on the prognosis of patients.
authors.affiliation: Department of Pathology and Radiotherapy/Oncology, Democritus University of Thrace, Alexandroupolis, Greece. targ@her.forthnet.gr
authors.forename: Michael I
authors.initials: MI
authors.lastname: Koukourakis
authors.forename: Alexandra
authors.initials: A
authors.lastname: Giatromanolaki
authors.forename: Efthimios
authors.initials: E
authors.lastname: Sivridis
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Gatter
authors.forename: Tanja
authors.initials: T
authors.lastname: Trarbach
authors.forename: Gunnar
authors.initials: G
authors.lastname: Folprecht
authors.forename: Michael M
authors.initials: MM
authors.lastname: Shi
authors.forename: David
authors.initials: D
authors.lastname: Lebwohl
authors.forename: Tarja
authors.initials: T
authors.lastname: Jalava
authors.forename: Dirk
authors.initials: D
authors.lastname: Laurent
authors.forename: Gerold
authors.initials: G
authors.lastname: Meinhardt
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D007770:L-Lactate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D000080864:Lactate Dehydrogenase 5; D045022:Lactate Dehydrogenases / Q000097:blood; D008297:Male; D008875:Middle Aged; D010793:Phthalazines / Q000627:therapeutic use*; D011379:Prognosis; D011725:Pyridines / Q000627:therapeutic use*; D016896:Treatment Outcome; D047368:Tumor Burden / Q000235:genetics
chemical_list: D020533:Angiogenesis Inhibitors; D007527:Isoenzymes; D010793:Phthalazines; D011725:Pyridines; C404768:vatalanib; D045022:Lactate Dehydrogenases; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5