title: Differential nucleobase protection against 5-fluorouracil toxicity for squamous and columnar cells: implication for tissue function and oncogenesis.
abstract: OBJECTIVE
  The goal of these studies was to test if local excess of a normal nucleobase substrate prevents the toxicity of protracted 5FU exposure used in human cancer treatment.
  
  
  METHODS
  Messenger RNA expression studies were performed of 5FU activating enzymes in human colon cancer cells lines (CaCo-2, HT-29), primary human gingival cells (HEGP), and normal esophageal and gastric clinical tissue samples. Excess nucleobase was then used in vitro to protect cells from 5FU toxicity.
  
  
  RESULTS
  Pyrimidine salvage pathways predominate in squamous cells of the gingiva (HEGP) and esophageal tissue. Excess salvage nucleobase uracil but not adenine prevented 5FU toxicity in HEGP cells. Pyrimidine de novo synthesis predominates in columnar Caco-2, HT-29 and gastric tissue. Excess nucleobase adenine but not uracil prevented 5FU toxicity to Caco-2 and HT-29 cells.
  
  
  CONCLUSIONS
  The directed application of the normal nucleobase uracil to the squamous cells of the oral mucosa and palms and soles together with the delivery of the normal nucleobase adenine to the columnar cells of the GI tract may enable the safe delivery of higher 5FU dose intensity. These results also suggest a feature of tissue function where squamous cells grow largely by recycling overlying tissue cell components. Columnar cells use absorbed surface nutrients for de novo growth. A disruption of this tissue function can result in growth derived from an underlying nutrient source. That change would also cause the loss of the region of cell turnover at the tissue surface. Subsequent cell proliferation with limiting nutrient availability could promote oncogenesis in such initiated tissue.
authors.affiliation: Department of Veterinary and Biomedical Sciences and Center for Molecular Toxicology and Carcinogenesis, Penn State University, 325 Life Sciences Building, University Park, PA, 16802, USA.|INDIGO Biosciences, Inc., 1981 Pine Hall Road, State College, PA, 16801, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Vanden Heuvel
authors.affiliation: Department of Veterinary and Biomedical Sciences and Center for Molecular Toxicology and Carcinogenesis, Penn State University, 325 Life Sciences Building, University Park, PA, 16802, USA.
authors.forename: Jerry T
authors.initials: JT
authors.lastname: Thompson
authors.affiliation: INDIGO Biosciences, Inc., 1981 Pine Hall Road, State College, PA, 16801, USA.
authors.forename: Prajakta
authors.initials: P
authors.lastname: Albrecht
authors.affiliation: Mount Nittany Medical Center, 1850 East Park Avenue, State College, PA, 16803, USA.
authors.forename: Donald
authors.initials: D
authors.lastname: Mandetta
authors.affiliation: Mount Nittany Medical Center, 1850 East Park Avenue, State College, PA, 16803, USA.
authors.forename: Harry
authors.initials: H
authors.lastname: Kamerow
authors.affiliation: Mount Nittany Medical Center, 1850 East Park Avenue, State College, PA, 16803, USA. jpfordmd@hotmail.com.|Asymmetric Therapeutics LLC, 141 Main St., PO Box J, Unadilla, NY, 13849, USA. jpfordmd@hotmail.com.
authors.forename: John P
authors.initials: JP
authors.lastname: Ford
mesh_terms: D000225:Adenine / Q000494:pharmacology*; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D004261:DNA Replication; D004847:Epithelial Cells / Q000187:drug effects; D004947:Esophagus / Q000166:cytology; D005472:Fluorouracil / Q000633:toxicity*; D005753:Gastric Mucosa / Q000166:cytology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D033702:Nucleobase Transport Proteins / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger; D014498:Uracil / Q000494:pharmacology*
chemical_list: D033702:Nucleobase Transport Proteins; D020011:Protective Agents; D011743:Pyrimidines; D012333:RNA, Messenger; D014498:Uracil; D000225:Adenine; C030986:pyrimidine; D005472:Fluorouracil
keywords: 5-fluorouracil; Cancer chemotherapy; Oncogenesis; Preclinical studies; Pyrimidine salvage; Toxicity prevention