title: O-6-methylguanine-deoxyribonucleic acid methyltransferase methylation enhances response to temozolomide treatment in esophageal cancer.
abstract: BACKGROUND
  World-wide, esophageal cancer is a growing epidemic and patients frequently present with advanced disease that is surgically inoperable. Hence, chemotherapy is the predominate treatment. Cytotoxic platinum compounds are mostly used, but their efficacy is only moderate. Newer alkylating agents have shown promise in other tumor types, but little is known about their utility in esophageal cancer.
  
  
  METHODS
  We utilized archived human esophageal cancer samples and esophageal cancer cell lines to evaluate O-6-methylguanine-deoxyribonucleic acid methyltransferase (MGMT) hypermethylation status and determined sensitivity to the alkylating drug temozolomide (TMZ). Immunoblot analysis was performed to determine MGMT protein expression in cell lines. To assess and confirm the effect of TMZ treatment in a methylated esophageal cancer cell line in vivo, a mouse flank xenograft tumor model was utilized.
  
  
  RESULTS
  Nearly 71% (12/17) of adenocarcinoma and 38% (3/8) of squamous cell carcinoma (SCC) patient samples were MGMT hypermethylated. Out of four adenocarcinoma and nine SCC cell lines tested, one of each histology was hypermethylated. Immunoblot analyses confirmed that hypermethylated cell lines did not express the MGMT protein. In vitro cell viability assays showed the methylated Kyse-140 and FLO cells to be sensitive to TMZ at an IC50 of 52-420 μM, whereas unmethylated cells Kyse-410 and SKGT-4 did not respond. In an in vivo xenograft tumor model with Kyse-140 cells, which are MGMT hypermethylated, TMZ treatment abrogated tumor growth by more than 60%.
  
  
  CONCLUSIONS
  MGMT methylation may be an important biomarker in subsets of esophageal cancers and targeting by TMZ may be utilized to successfully treat these patients.
authors: Department of Medicine, The University of Chicago, 5841 S Maryland Ave, MC 2115, Chicago, IL, USA.
authors: Rifat
authors: R
authors: Hasina
authors: Mosmi
authors: M
authors: Surati
authors: Ichiro
authors: I
authors: Kawada
authors: Qudsia
authors: Q
authors: Arif
authors: George B
authors: GB
authors: Carey
authors: Rajani
authors: R
authors: Kanteti
authors: Aliya N
authors: AN
authors: Husain
authors: Mark K
authors: MK
authors: Ferguson
authors: Everett E
authors: EE
authors: Vokes
authors: Victoria M
authors: VM
authors: Villaflor
authors: Ravi
authors: R
authors: Salgia
keywords: Alkylating agents; O-6-methylguanine-deoxyribonucleic acid methyltransferase hypermethylation; deoxyribonucleic acid repair genes; esophageal cancer; in vivo pre-clinical; response to treatment; temozolomide