Chemosensitivity prediction in esophageal squamous cell carcinoma: Novel marker genes and efficacy-prediction formulae using their expression data

Abstract

Abstract. Esophageal cancer is a highly lethal disease and the optimal therapy remains unclear. Since adjuvant chemotherapy gives a better chance of survival, we attempted to develop a chemosensitivity prediction model to improve individual responses to therapy. Comprehensive gene expression analyses (cDNA and oligonucleotide microarrays) and MTT assay of 8 drugs in 20 KYSE squamous cell carcinoma cell lines were performed to distinguish candidate marker genes whose expression levels reproducibly correlated with cellular drug sensitivities. After confirmation with real-time RT-PCR, we performed multiple regression analyses to develop drugsensitivity prediction formulae using the quantified expression data of selected marker genes. Using the same sets of genes, we also constructed prediction models for individual clinical responses to 5-FU-based chemotherapy using 18 cases. We selected 5 better marker genes, known as drug sensitivity determinants, identified 9 novel predictive genes for 4 of 8 anticancer drugs [5-FU, CDDP, DOX, and CPT-11 (SN-38)], and developed highly predictive formulae of in vitro sensitivities to the 4 drugs and clinical responses to 5-FU-based adjuvant chemotherapies in terms of overall and disease-free survivals. Our selected genes are likely to be effective drug-sensitivity markers and formulae using the 9 novel genes would provide advantages in prediction.

Selection of a novel drug-response predictor in esophageal cancer: A novel screening method using microarray and identification of IFITM1 as a potent marker gene of CDDP response

“…We applied microarray analysis and cytotoxic assay data of ESCC cell lines obtained in the previous study (12) to the new statistical analysis based on a two-dimensional mixed normal model (14) to explore the gene critically responsible for the 5-FU/CDDP efficacy with the following biological evidence.…”

“…All other chemicals were of analytical grade and were purchased from Wako Pure Chemicals (Osaka, Japan) and Sigma (St. Louis, MO, USA). The 20 KYSE human esophageal squamous cell carcinoma cell lines, (KYSE-30, -140, -150, -170, -180, -200, -220, -350, -410, -450, -510, -520, -590, -770, -850, -890, -1170, -1190, -1250, and -2270) were prepared as previously described (12). All cell lines were cultured in RPMI-1640 medium (Life Technologies, Inc., Grand Island, NY) containing 10% heat-inactivated fetal bovine serum (FBS; BioWhittaker, Verviers, Belgium) at 37˚C in a humidified atmosphere of 5% CO 2 and maintained in continuous exponential growth by passage every 3 days.…”

“…ESCC tissue specimens were collected at surgery from chemo-naïve patients with advanced esophageal cancer (TNM/UICC classification: Stage III or IV) as previously described (12). The patients received curative esophagectomy with the subsequent 5-FU/ CDDP combination chemotherapy as the post-operative adjuvant chemotherapy, and their prognosis and follow-up until August 1st, 2007 are presented.…”

“…The multifactorial mechanisms limit the prediction of individual drug response by any single marker including a 'snapshot expression profile' of microarray (6,9,10). Therefore, we have attempted to select a set of key marker genes using DNA microarray in vitro and developed a prediction system for clinical chemotherapeutic response through multiple regression analysis using expression data of the selected genes in several cancers, such as gastric, ovarian, and esophageal cancers (11)(12)(13). The observed predictive values of fixed formulae suggested that our attempts are likely a practical and potent approach to better prediction.…”

Histoculture drug response assay predicts the postoperative prognosis of patients with esophageal cancer

“…Although recent advances in molecular cellular biology have led to a better understanding of the mechanisms by which tolerance to anticancer agents is acquired and the molecular factors involved in chemosensitivity (17)(18)(19)(20), little information has been available regarding the prediction of chemosensitivity in clinical applications due to reliability, convenience and cost disadvantages.…”