Tadashi Torigoe

Radioimmunoassay for tumor antigen of human cervical squamous cell carcinoma

A heterologous antiserum for human cervical squamous cell carcinoma was prepared and specificity determined by Ouchterlony immunodiffusion and immunofluoresence studies. With this antiserum, a tumor antigen was purified from human cervical squamous cell carcinoma tissue. The specificities of the antigen and the antiserum were then re‐examined by a radioimmunoassay method using 125I‐labeled purified antigen. Although normal cervical tissue extract showed a moderate cross‐reactivity in the radioimmunoassay, the circulating antigen activity could not be detected in normal women or in several patients with other carcinomas, whereas 27 of 35 patients with cervical squamous cell carcinoma showed detectable serum antigen activity. All patients with advanced stages of cervical squamous cell carcinoma showed detectable antigen levels. These results indicate that there is a quantitative abnormality, at least, of this tumor antigen in patients with cervical squamous cell carcinoma and that the radioimmunoassay for the antigen is a potentially useful tool in clinical care.

Tumor-antigen TA-4 in the detection of recurrence in cervical squamous cell carcinoma

A radioimmunoassay for a tumor‐antigen (TA‐4) of squamous cell carcinoma was used to detect the recurrence in patients with squamous cell carcinoma of the uterine cervix. Of 17 patients who had recurrence, 15 cases showed reappearance of serum TA‐4 levels. Reappearance of serum TA‐4 was faster than other clinical signs of recurrence in 11 cases. These results indicated that TA‐4 assay would be a useful aid for the detection of recurrence in cervical squamous cell carcinoma.

Value of tumor-antigen (TA-4) of squamous cell carcinoma in predicting the extent of cervical cancer

The value of a tumor‐antigen (TA‐4) of squamous cell carcinoma in evaluating the extent of disease was studied in patients who primarily had surgical treatments with a diagnosis of cervical squamous cell carcinoma. Pretreatment serum TA‐4 levels were determined by a radioimmunoassay method. The extent of disease was determined by surgical evaluation and postoperative histologic examinations. Furthermore, all patients were followed for at least two years, and those patients who developed recurrence at the sites which were unresectable by radical hysterectomy were retrospectively regarded as the unresectable case. It was found that serum TA‐4 levels reflected the extent of disease, and that high pretreatment TA‐4 levels indicated the presence of the widespread tumor which was unresectable by radical hysterectomy.

Tumor antigen of human cervical squamous cell carcinoma. Correlation of circulating levels with disease progress

A double‐antibody radioimmunoassay method was used for serial determinations of a tumor‐antigen (TA‐4) of cervical squamous cell carcinoma, and the correlation of serum antigen levels with the disease progress was investigated in 23 patients with cervical squamous cell carcinoma. Ten cases with widespread metastases received radiotherapy and/or chemotherapy. Nine of these cases who showed progression of the disease had a corresponding increase in serum antigen levels, while one case who had regression of the disease showed a corresponding decrease in serum antigen levels. Thirteen patients received radical surgery, and in all of these, high pretreatment antigen levels declined to undetectable levels 1 or 2 weeks after surgery. A panel of coded sera from the NCI‐Mayo Clinic Serum Bank was also studied for evaluating the specificity of the assay. Thirteen of 25 patients (52%) with cervical squamous cell carcinoma showed positive serum antigen levels, while only one of 58 control cases (1.7%) showed false‐positive result. These results suggest that serial TA‐4 determinations may provide a useful method for evaluating regression or progression of the disease. Cancer 43:585–590, 1979.

Prognostic significance of the tumor antigen TA-4 in squamous cell carcinoma of the uterine cervix

Prognostic values of a tumor antigen (TA-4) of squamous cell carcinoma were studied in 135 patients with invasive squamous cell carcinoma of the uterine cervix. In order to evaluate the host defense responses against cancer, the percentage of lymphocytes (percentages of lymphocytes in total leukocyte counts in the peripheral blood) was also determined simultaneously in each case. All patients were followed up for 2 years. Sixty patients with Stage II disease underwent a radical operative procedure, and all other cases (75 cases) were treated primarily with radiation therapy. In both groups of patients, the survival rate or disease-free rate was significantly worse in those with TA-4 levels of greater than or equal to 15 microunits/ml compared to that of those with lower levels. The prognosis was particularly poor in those patients who had TA-4 levels of greater than or equal to 15 microunits/ml and lymphocyte percentages of less than 30. It was concluded that the simultaneous determinations of serum TA-4 and lymphocyte percentages would be useful in predicting the prognosis of cervical squamous cell carcinoma.

Flow cytometric analysis of tumor antigen TA-4 in cervical cytologic specimens

Flow cytometric analysis of cellular contents of TA‐4a tumor antigen of squamous cell carcinomawas performed in vaginal smears from 143 women. Abnormal findingscharacterized by a cell peak with high fluorescence intensityappeared in 85.7% of cases (54/63) of cervical squamous cell carcinoma80% of cases (4/5) of severe dysplasia42.9% of cases (3/7) of mild‐to‐moderate dysplasiaand in 20.6% of cases of healthy women (13/63). Cellular compositions sorted from abnormal cell fractions with high fluorescence intensity consistednot only of malignant cells but also of morphologically nonmalignant cells. Immunohistochemical studies indicated that these nonmalignant cells with high TA‐4 content originated from the intermediate layer of squamous epithelium adjacent to the cancer nest. These findings indicate that this method may be a useful approach for investigating some biologic characteristics of cells and for detecting cervical cancer or its precursors.

Abortifacient effect and uterine cervix-dilating action of 16,16-dimethyl trans Δ2 PGE1 methyl ester (ONO 802) in the form of a vaginal suppository (a randomized, double-blind, controlled study in the second trimester of pregnancy)

A newly synthesized 16, 16-dimethyl trans delta 2 PGE1 methyl ester (ONO 802) was clinically applied in the form of a vaginal suppository for therapeutic abortion of second trimester pregnancies. Its effects were studied in a double-blind test comparing it with an inactive placebo suppository. The study was conducted at 12 Japanese university hospitals. The number of patients was 125 in total, i.e. 63 receiving ONO 802 vaginal suppository (containing 1.0 mg ONO 802) and 62 receiving inactive placebo suppository. ONO 802 was more effective than placebo with a success rate of 87% (complete (71%) and incomplete (16%) abortions). The onset of uterine contractions was observed in 154.3+/-18.1 min. and the onset of uterine bleeding in 323.6+/-41.0 min. The expulsion of the fetus and placenta was observed in 955.4+/-97.0 and 961.6+/-97.0 min., respectively. The cervix dilating effect of ONO 802 was observed in 63.5% of the patients at 3 hours after the start of administration. Nausea, vomiting, abdominal cramps, diarrhea and pyrexia were noticed. However, all these side effects were transient and mild, requiring no treatment. No abnormality was observed in the puerperal course, duration of uterine bleeding or onset of subsequent menstruation following the therapeutic abortion. Therefore, the present study demonstrated that ONO 802 vaginal suppository was an effective and valuable drug for therapeutic abortion of second trimester pregnancies.

The role of domperidone in the regulation of prolactin release in rats.

Abstract Effects of domperidone, a dopamine antagonist, on prolactin release in female rats were studied. Oral administration of domperidone for 14 days caused a significant increase in serum prolactin levels in mature female rats. The routes by which domperidone exerted its effects on prolactin release were studied by a in vitro incubation system using rat pituitary tissues. Pituitary halves were incubated with (1) domperidone, (2) dopamine, (3) dopamine plus domperidone, (4) hypothalamic extracts from rats which had been treated with control meal (control hypothalamic extract), (5) control hypothalamic extract plus domperidone, and with (6) hypothalamic extract from rats which had been treated with domperidone for 14 days (domperidone-treated hypothalamic extract). Pituitary halves, when incubated alone, released a significant amount of prolactin into the incubation medium after 24 hours incubation, which was completely inhibited by dopamine or control hypothalamic extract. The addition of domperidone could not reverse the inhibitory effect of dopamine or control hypothalamic extract. On the other hand, domperidone-treated hypothalamic extract showed no inhibitory effects on prolactin release. These results indicated that domperidone could increase serum prolactin levels in female rats by acting primarily at the hypothalamus.

Use of bromocriptine in the treatment of normoprolactinemic infertility.

The efficacy of bromocriptine therapy was studied in 84 normoprolactinemic infertile patients. Bromocriptine (2.5-5.0 mg/day) was given for at least 1 month. Bromocriptine therapy was effective in 54 of 84 cases (64%), including 6 of 15 (40%) cases with amenorrhea, 16 of 24 cases (67%) with anovulatory cycle, 9 of 15 cases (60%) with delayed ovulation and 23 of 30 cases (77%) with luteal phase defect. Sixteen cases were able to conceive with bromocriptine alone. Twenty-five patients who did not respond to bromocriptine were treated with a combination therapy consisting of bromocriptine and clomiphene. Of the 25 cases, 14 responded to the therapy, and 6 of them were able to conceive. The response of prolactin to domperidone (10 mg, i.v.) was significantly (p less than 0.01) higher in the group responding to bromocriptine than in the nonresponding group. These results indicate that the administration of bromocriptine is an effective therapy for patients with normoprolactinemic endocrine disorders, and that domperidone may be useful in selecting the candidates for bromocriptine therapy.

Studies of factors affecting cellular TA-4 contents in cervical cancer.

TA-4産生培養細胞 (SKG-IIIa細胞) および子宮頸部扁平上皮癌細胞を用い, 細胞内TA-4量・核DNA量・細胞の大きさ (cellvolume) の相互関係についてtwo parameter flow cytometricanalysisにより検討した.細胞内TA-4量は, 細胞の大きさと明らかな相関関係を示したが, そのほかにもDNA量などcell cycle dependentな因子によつても影響を受けていることが明らかとなり, 細胞の機能またはその形態との相互関係を研究するうえで, TA-4は有力なパラメーターとなりうる可能性が示された.