Activation of H-ras is prevalent in 1,3-butadiene-induced and spontaneously occurring murine Harderian gland tumors.
Treatment of B6C3F1 mice with concentrations of 62.5-625 p.p.m. 1,3-butadiene by inhalation for up to 2 years causes a significantly increased incidence of Harderian gland (HG) neoplasms over untreated controls (Melnick,R., Huff,J., Chou,B.J. and Miller,R.A. Cancer Res., 50, 6592-6599, 1990). Since a specific K-ras mutation (codon 13 GGC-->CGC) had previously been described in lung and liver tumors from 1,3-butadiene-treated B6C3F1 mice, we analyzed 23 adenomas and six adenocarcinomas of the HG from mice exposed to 1,3-butadiene for this mutation and mutations in the H-ras gene. We also examined ras activation in 16 spontaneously occurring HG adenomas and one adenocarcinoma. DNA samples were prepared from paraffin-embedded tissues and analyzed by PCR followed by direct sequencing methods. Only one 1,3-butadiene-induced HG tumor contained the K-ras codon 13 mutation previously detected in lung and liver tumors. However, 16/29 HG tumors from the treated B6C3F1 mice contained H-ras codon 61 mutations. The mutations detected were: 12 CAA-->CGA transitions, two CAA-->CTA and two CAA-->AAA transversions. Eleven of 17 spontaneous HG tumors contained mutations in H-ras codon 61: five CAA-->CGA transitions, two CAA-->CTA transversions and four CAA-->AAA transversions. While the spectrum of ras mutations did not differ between the spontaneously occurring and chemically induced tumors, these data indicate that activation of H-ras contributes to the process of HG tumorigenesis in both groups of these neoplasms.
Fox Chase Cancer Center, Philadelphia, PA 19090.
T L
TL
Goodrow
W W
WW
Nichols
R D
RD
Storer
M W
MW
Anderson
R R
RR
Maronpot
D000818:Animals; D001483:Base Sequence; D002070:Butadienes / Q000633:toxicity*; D005786:Gene Expression Regulation; D011905:Genes, ras; D006243:Harderian Gland / Q000187:drug effects*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics*; D012376:Rodent Diseases / Q000235:genetics*
D002070:Butadienes; C031763:1,3-butadiene