Takahiko Gotoh

Chemoprevention of N-Nitroso-N-methylurea-induced Rat Mammary Carcinogenesis by Soy Foods or Biochanin A

We examined the effects of soybeans, a soy product (miso) and biochanin A, an isoflavone derivative, on N‐nitroso‐N‐methylurea (MNU)‐induced rat mammary carcinogenesis. Seven‐week‐old female CD/Crj rats received a single i.v. dose (40 mg/kg body weight) of MNU. After administration of MNU, rats were fed diet containing 0% (control), 2% or 10% soybeans, or 10% miso as a soy‐supplemented diet, or 10 or 50 mg/kg biochanin A. All rats were observed for 18 weeks after MNU administration. At 18 weeks, the multiplicity (mean tumors/rat) of palpable mammary tumors was significantly decreased in the 10% soybean (1.1) and 10% miso (1.2) diet groups compared to the control (2.2) (P<0.05, respectively). In the biochanin A‐supplemented diet groups, the incidence (percentage of rats with tumors) was significantly decreased in the 50 mg/kg (32%) diet group compared to the control (80%) (P<0.01), and the multiplicity was significantly decreased in both the 10 mg/kg (0.7) and 50 mg/kg (0.5) diet groups compared to the control (2.2) (P<0.01 and P<0.001, respectively). The proliferative cell nuclear antigen labeling index of mammary tumors was significantly decreased in both biochanin A‐supplemented diet groups compared to the control. The present results indicate that soybeans, miso, and biochanin A are useful for the prevention of mammary cancer.

Chemoprevention of N-nitroso-N-methylurea-induced rat mammary cancer by miso and tamoxifen, alone and in combination

We examined the effects of a Japanese fermented soybean product, miso, and tamoxifen (TAM), alone and in combination, on N‐nitroso‐N‐methylurea (MNU)‐induced rat mammary cancer. Seven‐week‐old female CD/Crj rats received a single i.v. dose (50 mg/kg body weight) of MNU. After administration of MNU, the rats were divided into 4 groups: regular diet (control), 10% miso diet, regular diet+TAM, and 10% miso diet+TAM. TAM was implanted s.c. in the form of pellets containing 2.5 mg at the same time as MNU was administered. All rats were observed for 18 weeks after MNU administration. Incidence (percentage of rats with tumors) and multiplicity (mean tumors/rat) of mammary tumors were 91% and 4.5 in the control, 77% and 2.4 (P<0.05) in the 10% miso group, 68% and 1.4 (P<0.01) in the TAM group, and 10% (P<0.0001 or less) and 0.2 (P<0.0001) in the 10% miso+TAM group. In the second experiment, the effect of the combination of miso and TAM on established rat mammary tumors was investigated. When the mammary tumors induced by MNU reached 10 to 25 mm, the rats were divided into 3 treatment groups: regular diet, regular diet+TAM, and 10% miso diet+TAM. At 6 weeks after the start of treatment, the mean tumor size in the control and TAM groups was 160% and 141% of the pretreatment value, but a decrease to 85% of the pretreatment value was produced by the combination of miso and TAM, and this was significantly different from both the control and TAM groups (P<0.01 and P<0.05, respectively). These results indicate that miso is useful in protecting against mammary cancer and it can be expected to have a potent antitumor effect, especially when used in combination with TAM.

Influence of Paternal 252Cf Neutron Exposure on Abnormal Sperm, Embryonal Lethality, and Liver Tumorigenesis in the F1 Offspring of Mice

Experiments were conducted to determine whether neutron‐induced genetic damage in parental germline cells can lead to the development of cancer in the offspring. Seven‐week‐old C3H male mice were irradiated with 252Cf neutrons at a dose of 0, 50, 100, or 200 cGy. Two weeks or 3 months after irradiation, the male mice were mated with virgin 9‐week‐old C57BL females. Two weeks after irradiation, the irradiated male mice showed an increased incidence of sperm abnormalities, which led to embryo lethalities in a dose‐dependent manner when they were mated with unirradiated female mice. Furthermore, liver tumors in male offspring of male mice in the 50 cGy group were significantly increased in 19 of 44 (43.2%) animals, in clear contrast to the unirradiated group (1 of 31; 3.2%) (P < 0.01). In the 100 cGy group, 6 of 39 (15%) mice had lesions. At 3 months after irradiation abnormal sperm and embryonal lethality were not significantly increased. The incidences of liver tumors in male offspring from the 50 cGy, 100 cGy and 200 cGy groups were 6 of 20 (30%), 5 of 22 (23%) and 1 of 19 (5%), respectively, which are not significantly increased compared with the control. It is concluded that increased hepatic tumor risk in the F1 generation may be caused by genetic transmission of hepatoma‐associated trait(s) induced by 252Cf neutron irradiation.

Effects of Miso in Reducing Risk of Liver and Gastric Tumors in Experimental Animals

When intact male C3H or 252Cf neutron irradiated B6C3F1 mice were fed on a diet containing 10% miso for 13 months, the frequency and multiplicity of liver tumors were significantly reduced in both cases. In irradiated females only a tendency for a similar reduction was observed. B6C3F1 male mice i.p. injected once with diethylnitrosamine (DEN) at 15 days of age and exposed to neutrons at four weeks of age also demonstrated a significantly decreased multiplicity of liver tumors when given a diet supplemented with either 10% miso or 20ppm biochanin A (5,7-dihydroxy-4-methoxyisoflavone). In Sprague-Dawley (CD) rats treated with 100ppm N-methyl-N’ nitro-N-nitrosoguanidine (MNNG) for 16 weeks in their drinking water, the net incidence of gastric tumors per mg MNNG intake was reduced with a miso-supplemented diet. In addition, when six-week-old rats were given s.c. injections of azoxymethane (AOM, 15mg/kg body weight) once a week for three weeks, and fed on diets containing 5%, 10%, or 20% miso and 10ppm biochanin A from five weeks of age, the numbers of aberrant crypt foci four weeks after the first administration of AOM were decreased with increasing miso in a dose-dependent manner. The present results indicate that administration of a miso-supplemented diet may inhibit the development of liver and gastric tumors, as well as aberrant crypt foci, in experimental animals.

Early Breast Cancer Following Treatment of Myelodysplastic Syndrome: Report of a Case

A 45-year-old woman was admitted to our hospital complaining of a mass in her left breast. She had previously been diagnosed with myelodysplastic syndrome (MDS), a type of refractory anemia, based on bone marrow findings and chromosome analysis. She received a preoperative transfusion of fresh packed platelets and a recombinant human granulocyte colony-stimulating factor (rhG-CSF) injection. Left partial mastectomy and axillary lymph nodes dissection were performed to treat early breast cancer. Postoperatively, prophylactic radiotherapy of the residual breast and administration of medroxyprogesterone acetate (MPA) were performed because the tumor tissue was positive for progesterone receptors. She has remained clinically stable, with no evidence of recurrence, for more than three years to date. We report a rare case of breast cancer with MDS, treated with breast-conserving therapy. The strategy of pre- or postoperative platelet transfusion, rhG-CSF injections, and hormonal therapy (AAPA) appears to be suitable treatment for progesterone receptor (PgR)-positive breast cancer patients with AADS.

Significance of Mass Screening for Simultaneous Thyroid Disease and Breast Cancer

乳癌集団検診における甲状腺同時検診の意義について, 当教室の甲状腺疾患合併乳癌症例を併せて検討した。広島県集団検診では, 1985年より1991年の間にのべ約27万人の30歳以上の女性を対象として, 乳癌146人と甲状腺癌56人を発見した。その発見率はそれぞれ0.05%, 0.02%であった。発見乳癌および甲状腺症例の平均年齢はいずれも約50歳で, 年齢別発生率にも差を認めなかった。一方, 広島大学第2外科において1965年から1991年末までに加療した原発性女性乳癌506症例中, 確診の得られた甲状腺疾患合併症例は32例, 6.3%であった。そのうち特に甲状腺癌および甲状腺機能亢進症がそれぞれ10例と多く見られた。また甲状腺疾患合併群には比較的早期の乳癌が多く, 逆に進行例が少ない傾向が見られ, したがってその生存率も非合併群に比して比較的良好であった。甲状腺疾患と乳癌発生のリスクに関しては依然として未解明な点も多く, また今回, 甲状腺機能検査値からは明らかな相違を見出せなかった。しかし乳腺疾患と同様, 甲状腺疾患も女性に多い疾病の1つとしてまったく無関係とは言い難く, また重複癌例では乳癌家系や両側乳癌例, 被爆例が多いなど両者の発生要因として, 共通の内分泌あるいは遺伝・環境因子の関与が示唆された。したがって乳癌検診時に同時に甲状腺の視・触診を行うこと, また甲状腺疾患の既往などを十分聴取することの意義は大いにあるものと考えられた。