Enhancement of tongue carcinogenesis in Hras128 transgenic rats treated with 4-nitroquinoline 1-oxide.
Transgenic rats carrying human c-Ha-ras proto-oncogene (Hras128 rats) have been shown to be highly susceptible to induction of tumors. We have found an early induction of tongue tumors in Hras128 rats treated with 4-nitroquinoline 1-oxide (4NQO). 4NQO was administered to the Hras128 and wild-type Sprague-Dawley (SD) rats for 4 and 8 weeks, respectively. The experiment was terminated at 14 (Hras128 rats) and 28 (SD rats) weeks. Either during or after treatment with 4NQO, dysplastic hyperplasia, papilloma and squamous cell carcinoma were found on the tongue of both Hras128 and wild-type rats, with a higher incidence and multiplicity in Hras128 rats. Treatment of the Hras128 rats with 4NQO significantly increased cell proliferation in the tumor compared to the control rats. In the tongue tumors of the Hras128 rats, there was a significant increase in the mRNA expression levels of cyclin D1 and COX2. To examine whether this experimental system is useful for screening of the candidate agents for cancer preventive effect, nimesulide, a selective COX2 inhibitor, was tested in the present model. Nimesulide significantly decreased total multiplicity of tongue lesions compared to the control rats. Treatment of Hras128 rats with nimesulide caused a significant decrease in the levels of mRNA expression of cyclin D1 and COX2 in the tumor. Therefore, the current 4NQO-induced Hras128 rat tongue carcinogenesis model provides a simple and rapid system for investigating carcinogenesis process and evaluating the effect of possible cancer preventive agents for human tongue cancer.
Naoi
Kuniko
K
Department of Medical Therapeutics and Molecular Therapeutics, Gifu Pharmaceutical University, Gifu, Japan.
Sunagawa
Nao
N
Yoshida
Ichiro
I
Morioka
Takamitsu
T
Nakashima
Makoto
M
Ishihara
Masashi
M
Fukamachi
Katsumi
K
Itoh
Yoshinori
Y
Tsuda
Hiroyuki
H
Yoshimi
Naoki
N
Suzui
Masumi
M
D015112:4-Nitroquinoline-1-oxide / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced* / Q000453:epidemiology / Q000235:genetics* / Q000401:mortality; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics*; D004357:Drug Synergism; D020022:Genetic Predisposition to Disease; D006801:Humans; D015994:Incidence; D008297:Male; D010212:Papilloma / Q000139:chemically induced / Q000453:epidemiology / Q000235:genetics / Q000401:mortality; D000090063:Proto-Oncogene Mas; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D014062:Tongue Neoplasms / Q000139:chemically induced* / Q000453:epidemiology / Q000235:genetics* / Q000401:mortality
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D015112:4-Nitroquinoline-1-oxide; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)