Adv Pharm Bull. 2019;9(3):439-444.
doi: 10.15171/apb.2019.052
  Abstract View: 24
  PDF Download: 31

Research Article

Dihydropyrimidine Dehydrogenase Levels in Colorectal Cancer CellsTreated with a Combination of Heat Shock Protein 90 Inhibitor andOxaliplatin or Capecitabine

Mahshid Mohammadian 1, Shima Zeynali-Moghaddam 1, Mohammad Hassan Khadem Ansari 1, Yousef Rasmi 1 ORCiD, Anahita Fathi Azarbayjani 2 ORCiD, Fatemeh Kheradmand 1,3 * ORCiD

1 Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical sciences, Urmia, I.R. Iran.
2 Department of Pharmaceutics, School of Pharmacy, Urmia University of Medical sciences, Urmia, I.R. Iran.
3 Solid Tumor Research Center and Cellular and Molecular Research Center, Urmia University of Medical sciences, Urmia, I.R. Iran.

Abstract

Purpose: Dihydropyrimidine dehydrogenase (DPD) is the principal enzyme in the catabolismof fluoropyrimidine drugs including capecitabine. A recent report has suggested that oxaliplatinchemotherapy is associated with elevated DPD levels and chemoresistance pattern. As a newlydeveloped chemotherapeutic agent, 17-allyloamino-17-demethoxy-geldanamycin (17-AAG)can be effective in combination therapy with oxaliplatin and capecitabine in colorectal cancer(CRC). DPD expression level can be a predictive factor in oxaliplatin and capecitabine-basedchemotherapy. We evaluated DPD in mRNA and protein levels with new treatments: 17-AAG incombination with oxaliplatin and capecitabine in HT-29 and HCT-116 cell lines.Methods: Drug sensitivity was determined by the water-soluble tetrazolium-1 assay in aprevious survey. Then, we evaluated the expression levels of DPD and its relationship with thechemotherapy response in capecitabine, oxaliplatin, and 17-AAG treated cases in single andcombination cases in two panels of CRC cell lines. DPD gene and protein expression levels weredetermined by real-time polymerase chain reaction and western blotting assay, respectively.Results: DPD gene expression levels insignificantly increased in single-treated cases versusuntreated controls in both cell lines versus controls. Then, the capecitabine and oxaliplatinwere added in double combinations, where DPD gene and protein expression increased incombination cases compared to pre-chemotherapy and single drug treatments.Conclusion: The elevated levels of cytotoxicity in more effective combinations could be relatedto a different mechanism apart from DPD mediating effects or high DPD level in the remainingresistance cells (drug-insensitive cells), which should be investigated in subsequent studies.
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Submitted: 10 Sep 2018
Revised: 27 Apr 2019
Accepted: 20 May 2019
First published online: 01 Aug 2019
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