N-nitrosocimetidine as an initiator of murine skin tumors with associated H-ras oncogene activation.
N-Nitrosocimetidine (NCM) is a derivative of the drug cimetidine, a methylguanidine derivative used in the treatment of peptic ulcer, and is known to be inactive as a complete mouse skin carcinogen, even when given in repeated high doses for a long period. In the current experiment, NCM was tested for its ability to initiate skin tumors on Sencar mice. It was applied at doses of 1 or 0.3 mg, 5 times/week for 6 weeks, followed by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), 1 microgram, 2 times/week for 50 weeks. Controls received acetone. The higher NCM dose had significant effects on TPA-promotable tumors, resulting in shortened time to first tumor, increased incidence of all tumors (2-fold) and of malignant tumors (4-fold), and greater tumor growth rate (2-fold), compared with the acetone/TPA-treated mice. The mice given the lower NCM dose did not exhibit increased tumor incidence, but their tumors had a significantly higher growth rate (3-fold) than those of the TPA controls. NCM without TPA treatment caused no tumors. Thus, NCM is a definitive, though weak initiator of TPA-promotable tumors. Nine tumors from the NCM-treatment groups were analyzed for activated oncogenes by the NIH 3T3 cell transfection assay. Five were positive and four of these were found by selective oligonucleotide hybridization analysis to have an A to T transversion in the second position of codon 61 of the H-ras oncogene. One of two tumors from the acetone/TPA group also contained transforming DNA and demonstrated this mutation. None of the tumors had a G----A transition mutation at the second position of codon 12 of this oncogene. Tumor initiation by NCM may then be associated with the same oncogene mutation reported for mouse skin tumors initiated by other types of carcinogens, although occurrence of the mutated oncogene in TPA controls precludes a definitive conclusion.
Anderson
L M
LM
Division of Cancer Etiology, NCI-Frederick Cancer Research Facility, MD 21701.
Enomoto
T
T
Perantoni
A O
AO
Riggs
C W
CW
Kovatch
R M
RM
Reed
C D
CD
Giner-Sorolla
A
A
Rice
J M
JM
D000818:Animals; D002273:Carcinogens; D002927:Cimetidine / Q000031:analogs & derivatives*; D003043:Cocarcinogenesis; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D051379:Mice; D009154:Mutation; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D016019:Survival Analysis; D013755:Tetradecanoylphorbol Acetate
D002273:Carcinogens; C019503:nitrosocimetidine; D002927:Cimetidine; D013755:Tetradecanoylphorbol Acetate