Absence of Ki-ras mutations in exocrine pancreatic tumors from male rats chronically exposed to gabapentin.
Human pancreatic malignancies originating from duct cells most frequently demonstrate activation of Ki-ras gene by G-to-A transition at codons 12 and 13. Rat pancreatic exocrine tumors more frequently and almost exclusively derive from acinar cells and thus differ morphologically from human pancreatic neoplasms. Male Wistar rats fed with 2% gabapentin (1-(aminomethyl)cyclohexane acetic acid) in diet for 2 years developed pancreatic exocrine adenomas and adenocarcinomas. To study the mutations in Ki-ras gene, rat pancreatic proliferative lesions induced by gabapentin were retrospectively analyzed by PCR amplification of DNA isolated from paraffin sections of formalin-fixed rat pancreatic adenomas and adenocarcinomas, using specific primers for regions encoding exon 1 (codon 12/13) and exon 2 (codon 61). The amplified 110-bp fragments of exon 1 and exon 2 were analyzed for mutations at codon 12/13 and 61. The results showed Ki-ras mutations at codon 12 in human pancreatic carcinomas. Novel mutations GGT-to-TGT and GGT-to-CGT were detected at codon 12 in 1/5 and 2/5 human pancreatic tumors. Rat adenomas or carcinomas induced by gabapentin expressed wild type sequences at codons 12, 13 and 61. These findings were confirmed by allele-specific oligonucleotide hybridization, single-strand confirmation polymorphism of exon 1 and direct sequencing of exon 1 and exon 2. The absence of mutations in these rat pancreatic tumors suggests that these tumors do not correspond to the human tumors, and that the pathogenesis of this rodent tumor formation may follow different molecular mechanisms.
Fowler
M L
ML
Department of Pathology & Experimental Toxicology, Parke-Davis Pharmaceutical Research, Warner-Lambert Co., Ann Arbor, MI 48105.
Sigler
R E
RE
de la Iglesia
F A
FA
Reddy
J K
JK
Lalwani
N D
ND
D000085:Acetates / Q000633:toxicity*; D000230:Adenocarcinoma / Q000139:chemically induced / Q000235:genetics; D000236:Adenoma / Q000139:chemically induced / Q000235:genetics; D000588:Amines; D000818:Animals; D001483:Base Sequence; D003062:Codon / Q000235:genetics; D003509:Cyclohexanecarboxylic Acids; D004273:DNA, Neoplasm / Q000235:genetics; D000077206:Gabapentin; D011905:Genes, ras; D006965:Hyperplasia; D008297:Male; D008969:Molecular Sequence Data; D010179:Pancreas / Q000187:drug effects / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000139:chemically induced* / Q000235:genetics; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D051381:Rats; D017208:Rats, Wistar; D005680:gamma-Aminobutyric Acid
D000085:Acetates; D000588:Amines; D003062:Codon; D003509:Cyclohexanecarboxylic Acids; D004273:DNA, Neoplasm; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D016283:Proto-Oncogene Proteins p21(ras)