Phorbol ester facilitates apoptosis in murine fibroblasts pretreated by mild ultraviolet radiation.

Although phorbol 12-myristate 13-acetate (PMA) inhibits apoptosis and promotes the growth of some types of cells, it induces apoptosis in other cells. We evaluated the apoptotic effects of PMA on murine fibroblasts (L-929) that had been exposed to ultraviolet-B (UV-B) radiation at 312 nm, which promotes tumor cell growth. Exposure to PMA alone did not induce Fas, Fas-L, or apoptosis. Cells exposed to mild UV-B irradiation (80 J/m(2)) alone exhibited a slight expression of Fas and Fas-L 36 to 48 h after the exposure, and exhibited apoptosis as evidenced by DNA fragmentation 72 h after exposure. The addition of PMA (0.8 x 10(-5) to 3.2 x 10(-5) M) to the medium 24 h after the UV-B exposure markedly and dose-dependently enhanced these cell responses. Confluent untreated cells, cells cocultured with PMA, and cells cocultured with PMA for 24 h after the UV-B exposure consistently expressed mRNAs for wild-type p53, bcl-2, and ICE. Expression of c-myc mRNA was initially observed, but became undetectable in the cells cocultured for 24 h with a high concentration of PMA (3.2 x 10(-5) M) following UV-B exposure. Such cells subsequently exhibited the maximal apoptotic response. We conclude that mild exposure to UV-B altered murine fibroblast cells in such a way as to facilitate their death by apoptosis upon addition of PMA.

Clinical evaluation of tumor-associated mucin-type glycoprotein CA 54/61 in ovarian cancers: comparison with CA 125.

Studies were conducted in 343 women on the clinical utility of the newly developed tumor-associated mucin-type glycoprotein, CA 54/61, as a tumor marker in serum for ovarian cancer. The overall positivity rate of the new marker was 60%, lower than the rate of 88% obtained with CA 125 measured concurrently. Concerning tumor histology, CA 54/61 had a positivity rate of 78% in mucinous adenocarcinoma, compared with 44% with CA 125. There was no correlation between the serum levels of CA 54/61 and CA 125 (r = 0.05). CA 54/61 showed a low rate of positivity in benign disease and only exceeded the cutoff value in one patient with an endometrial cyst, whereas CA 125 had a positivity rate of 60%. The false-positive rates for CA 125 during the first trimester of pregnancy and during menstruation were 57 and 16%, respectively, whereas the rates for CA 54/61 were only 11 and 5%, respectively. Assay of both CA 54/61 and CA 125 increased the success rate in diagnosing ovarian cancer to 95% (38 of 40 patients).

Arrest of follicular development in a patient with 17 alpha-hydroxylase deficiency: folliculogenesis in association with a lack of estrogen synthesis in the ovaries.

The degree of follicular development was examined in a patient with 17 alpha-hydroxylase deficiency that accounted for impairment of estrogen and androgen biosynthesis. The ovarian content of P was markedly higher than those of any other steroids requiring 17 alpha-hydroxylation for synthesis. The morphologic analysis of the ovaries demonstrated that normal follicles could not develop to more than 2.2 mm in diameter, and most follicles with diameters of 1.0 mm or more yielded to atresia. It is known that estrogen and FSH act synergistically on the growth of the follicles. Our data suggest that the follicles can develop up to the size of 2.2 mm in diameter at most with the sole stimulation of gonadotropin.

Cancer-associated retinopathy in a patient with endometrial cancer.

PURPOSE: We studied a case of unusual retinopathy in a 60-year-old woman. METHOD: The patient developed bilateral retinopathy with iridocyclitis and vitreitis. Corticosteroid therapy could not prevent deterioration of visual acuity and field. The electroretinogram became nonrecordable, and fluorescein angiogram exhibited retinal pigment epithelium window defects, fluorescein stainings to the vascular walls, and narrowed arterioles. RESULTS: The patient underwent hysterectomy and lymphadenectomy for endometrial cancer in the corporis uteri. She was found to possess antibodies against retinal 34-kd protein, leading to a diagnosis of cancer-associated retinopathy. CONCLUSION: Cancer-associated retinopathy may occur in patients with endometrial cancer of the corporis uteri.

Apoptosis as a criterion for sensitivity of uterine cervical adenocarcinoma to cisplatin.

Two patients with uterine cervical adenocarcinoma received two courses of intra-arterial cisplatin administration. In the specimens of cervix 24 or 48 h after chemotherapy, marked apoptosis were observed. These bulky cervical tumors almost disappeared, and good PRs were confirmed by CT before operation. Apoptosis which is observed in the tissues of cervical adenocarcinoma 24 or 48 h after intra-arterial infusion of cisplatin, might be a new criterion of this chemotherapy effect.

Radical cytoreductive surgery combined with platinums-carboplatin and cisplatin chemotherapy for advanced ovarian cancer.

In an attempt to improve the therapeutic outcome for patients with advanced ovarian cancer, primary radical cytoreductive surgery consisting of hysterectomy, bilateral salpingo-oophorectomy, omentectomy and retroperitoneal lymph node resection, with optimal cytoreduction in case of metastatic lesions, was followed by five courses of chemotherapy of carboplatin 280 mg/m2 i.v. on day 1 and cisplatin 70 mg/m2 i.v. on day 2, every four weeks. A total of 51 patients with advanced epithelial ovarian cancer comprised the study (6 with stage IIC, 32 with stage III, and 13 with stage IV). Following radical cytoreductive surgery, 29 patients (57%) showed 2 cm or less of residual disease. There was a low incidence of severe complications and no postoperative mortality. An overall response rate of 76% of patients consisting of 42% pathologic complete response and 34% partial response was observed. The overall four-year survival rate for patients with stage III cancer was 70%. The dose-limiting toxicity was identified to be hematologic toxicity, which showed grade 3/4 of leuopenia 37% (neutropenia 73%) and thrombocytopenia 24%. The incidence of peripheral neurotoxicity was comparatively low. An evaluation of nerve conduction velocity revealed that motor neurotoxicity was liable to appear in the lower extremity, while sensory nerve damage was often noted in the periphery in both the upper and lower extremities. The combined chemo-surgery treatment resulted in good response and good survival without fatal toxicity for patients with advanced ovarian cancer.

[Establishment and characterization of a human undifferentiated carcinoma cell line (HMG)].

The undifferentiated carcinoma cell line (HMG) was established from a nude mouse tumor which had been produced by transplantation of a intraperitoneal tumor of 27-year-old woman. The HMG cell line has the following biological properties. 1. The HMG cells are round to oval in shape and grow as floating cell aggregates like a rouleau or a cluster of grapes. 2. 100 passages have been carried out over a year, and the population doubling time is about 17 hrs. 3. In the original tumor, keratin and vimentin were expressed simultaneously, in HMG cells, however, only localization of vimentin was confirmed. 4. By chromosomal analysis, over 90% of the cells revealed 46, XX, with no karyological abnormalities, at passage 82. 5. When heterotransplanted into the subcutis of a nude mouse, HMG cells produced a undifferentiated carcinoma resembling the original tumor.

Comparison of the effects of whey mineral complexes on bone metabolism in male growing rats.

The effects of whey mineral complexes (WMC1 and WMC2) on bone metabolism were studied in male growing rats. The contents of Ca, P, and protein in WMC1 were 18.2, 8.4, 2.3%, respectively, whereas those of WMC2 were 26.4, 14.6, and 10.5%, respectively. WMCs were added to diets as a sole source of Ca: the levels of dietary Ca were 0.3 and 0.6%. CaCO3 was used as a reference. There was no difference in body weight gain and quantitative values for Ca balance among the groups at the same level of dietary Ca. Rats fed WMC2 had a higher femoral Ca and bone density of humerus. The bone properties in rats fed WMC1 were not as high as those in rats fed WMC2. The P absorption and absorption rate were affected significantly by the type of dietary Ca source as well as the levels of dietary Ca. The percent of tubular reabsorption of P of rats fed WMC1 or WMC2 had a tendency to be higher than that of rats fed CaCO3 at each dietary Ca level. The results of urinary cAMP excretion showed that the parathyroid hormone function in rats fed WMC2 was relatively lower. The differences in minerals and other constituents between WMC1 and WMC2 are discussed from the viewpoint of bone metabolism.

[Remnant-like particles-cholesterol (RLP-C) assay and its clinical application to lipid tests in a postprandial as well as fasting state].

It was during the past few years that postprandial hyperlipidemia is believed to be more closely related to a risk for coronary artery disease. However, the high variability in the postprandial triglyceride (TG) levels could have made overlooked such diagnostic value in estimating an individual's risk for coronary artery disease. To minimize the impact of such variability, the remnant lipoproteins, TG-rich lipoproteins, might be measured in cholesterol using remnant-like particles (RLP-C) assay as a more reliable marker. In place of the previous cholesterol reagent (CHOD-Iodine) in RLP-C assay, the RLP-C assay was improved by employing a new cholesterol reagent (POD-EMSE). The correlation between these two assays was high (r = 0.978). The variations in RLP-C levels in healthy normolipidemic subjects was within 7.5mg/dl in a day. In oral-fat loading test, the variations of RLP-C levels in healthy subjects were also within 7.5mg/dl. However, patients with coronary artery disease showed much higher levels (over 7.5mg/dl) of RLP-C during the test. In conclusion the RLP-C assay can be used for the measurement of remnant lipoproteins in serum prepared from the fasting as well as postprandial states for predicting subjects who may be at risk of coronary artery disease.

[Level of 5-FU in cancerous and normal tissues of nude mice after oral administration of tegafur coadministered with uracil (UFT)].

In order to investigate the effect of UFT, a new antitumor agent, 5-fluorouracil (5-FU) levels in serum and various tissues were measured by the gas chromatographic-mass fragmentographic method. The subjects used for the study were nude mice which had received implants of human endometrial carcinoma. The results were as follows: As compared with tegafur, the concentration of 5-FU in serum rose quickly when UFT was administered, and the values were clearly high. The concentration of 5-FU obtained in tumor tissues with the use of UFT were 2.5 times higher than those obtained by the use of tegafur. Even with one third of the dose of UFT, values were still 1.5 times higher. In normal tissues, the administration of UFT against that of tegafur resulted in higher concentrations of 5-FU. On the other hand, when one third of the dose of UFT was used, 5-FU concentrations in major organs, such as the liver or kidney, showed clearly low values. Based on these findings, it became clear that the 5-FU concentration in tumor tissue is specifically raised by tegafur coadministered with Uracil (UFT), while such an effect is prevented from proceeding in normal tissue.

[Level of 5-FU in uterine cervical cancer tissue after oral administration of UFT].

We measured concentrations of 5-FU in cancerous and normal cervical tissues in 16 patients with cervical cancer to whom UFT or tegafur had been administered. The results were as follows: Concentrations of 5-FU in cancerous tissues measured 30 minutes and 2 hours after UFT administration were 0.181 +/- 0.034 microgram/g and 0.562 +/- 0.145 micrograms/g respectively, while in patients to whom tegafur had been administered, they were 0.105 +/- 0.030 microgram/g and 0.126 +/- 0.015 microgram/g respectively. The comparison of 5-FU concentrations in cancerous tissues within each individual patient indicated that the value was higher after UFT administration than after tegafur administration in 13 cases (81.3%). When classified by histological typing, cases of non-keratinizing carcinoma showed the highest value, followed by keratinizing cases and adenocarcinomas, which indicated the lowest value with administration of UFT. However, there were no differences among these three types when tegafur was administered. Based on the above findings, it was indicated that UFT is an antitumor agent with a higher tumor specificity, especially in non-keratinizing carcinoma.

[Estrogen production by epithelial ovarian tumors and dermoid cyst].

The estrogen-producing activity was investigated in subjects with common epithelial tumors and dermoid cysts, which were not included in the category of hormone-producing tumors. Serum estradiol (E2) in peripheral blood of patients with ovarian tumors were assayed pre-and post-operatively. In addition, cytological examinations of vaginal smears and histological examinations of the endometrium were carried out. The results were as follows: The mean of preoperative serum E2 levels in postmenopausal cases (16) was 230.9 +/- 248.5pg/ml, which was significantly higher than the control of the same age group (p less than 0.01). In seven (63.3%) out of 11 cases followed up, a distinct postoperative decline was indicated in the serum E2 level. The mean of preoperative serum E2 levels in 28 cases of premenopause collected in the early follicle phase was 135.6 +/- 148.8pg/ml, which was apparently higher than the level in normal females in the follicle phase. Also, an evident decline was observed postoperatively in the E2 level in 8 (40%) out of 20 cases. The cytological observations of vaginal smears in 44 cases of postmenopausal ovarian tumor provided the following results: The karyopyknotic index was 12-23% on the average in each age group, which was comparatively higher than that of the control. The maturation index also indicated a deviation to the right compared to the control. The following were the results of histological examinations of the endometrium carried out in 23 cases of postmenopausal ovarian tumor: 5 cases (21.7%) of proliferative endometrium; 3 cases (13.0%) of cystic hyperplasia and 2 cases (8.7%) of adenomatous hyperplasia.(ABSTRACT TRUNCATED AT 250 WORDS)

Thymidylate synthase inhibition as a predictor of tumor sensitivity of fluorinated pyrimidines.

The thymidylate synthase (TS) content of tumor tissue was assayed and the levels of 5-fluorouracil (5-Fu) in serum and tumor tissue were determined in 21 patients with cervical cancer who were treated with UFT, a fluorinated pyrimidine. Subrenal capsule assay, a predictive tumor sensitivity test, was conducted concurrently on cervical tumor samples. TS inhibition and serum and tissue 5-Fu levels widely varied between both samples. Investigation of the relationship between the tumor growth inhibition rate determined by subrenal capsule assay and the above parameters (TS inhibition, serum and tissue 5-Fu levels) showed that TS inhibition and tumor growth inhibition were well correlated (r = 0.73). This suggests that a TS inhibition assay in tumor tissue can be a useful predictive test for tumor sensitivity of fluorinated pyrimidines.

Estrogen producing activity in epithelial ovarian tumors and dermoid cysts.

In 28 cases of postmenopausal women with non-functioning ovarian tumors, the estradiol (E2) level was assayed in peripheral plasma and tumor tissue extract. E2 precursors were also assayed in the tissue extract, and localization of 3beta-hydroxysteroid dehydrogenase (3beta-HSD) in the tissue was investigated. The plasma E2 levels were 153.8 +/- 205.9 pg/ml in 15 benign tumor cases, 244.3 +/- 336.5 pg/ml in 13 malignant tumor cases, and both of which were significantly higher than 12.3 +/- 3.6 pg/ml in normal postmenopausal women (p less than 0.01). The postoperative plasma E2 level (33.3 +/- 32.7 pg/ml) was significantly lower than the preoperative one (228.3 +/- 319.0 pg/ml). Twelve of 19 cases (68.2%) showed a postoperative decline in the E2 level to less than a half of the preoperative level. E2 and its precursors were found in tumor tissue. These findings demonstrate that E2 is produced by the tumor tissue itself. In addition, 3beta-HSD activity was localized in the stroma of ovarian tumors, indicating that E2 synthesis is mainly carried out in stromal cells rather than in epithelial cells.

Protective effect of elastase on cis-platinum-induced renal toxicity.

The protective effects of elastase (Ela) and fosfomycin against renal toxicity of cis-diamminedichloroplatinum (II) (CDDP) were evaluated in an experimental study using rats. When Ela was used concomitantly with CDDP, the elevation of urinary N-acetyl-beta-D-glucosaminidase levels in the early phase and the sharp fall in these levels in the latter phase were prevented. It was also found that the blood urea nitrogen levels and serum creatinine levels were significantly lowered. Histologically, atrophic and necrotic changes in the tubular epithelium were prevented. The total serum platinum levels showed no change with the addition of Ela; however, the platinum levels in the renal tissues were significantly reduced. These results suggested that Ela is effective against platinum deposits in the renal tissues, particularly in the tubular epithelium, thus protecting the kidneys. On the other hand, fosfomycin demonstrated no such positive results suggestive of a protective effect on the renal function parameters or during histological observation.

Combined effects of S-1, a new form of oral tegafur, plus modulators on ovarian cancer in nude rats.

We evaluated the efficacy of S-1 as a new oral antitumor agent in ovarian cancer-bearing nude rats. This drug consists of tegafur, 5-chloro-2,4-dihydroxypyridine, and oxonic acid in a molar ratio of 1:0.4:1.S-1 was given alone or in combination with cisplatin. When administered alone at a daily dose of 20 mg/ kg, S-1 produced a significant inhibition of tumor growth [inhibition rate (IR) 89%] in the treated versus the control animals (p < 0.05). The effects of S-1 resembled those of cisplatin-treated groups. The consecutive daily administration of S-1, 20 mg/kg, combined with cisplatin, 1 mg/kg, markedly inhibited cell growth (IR 99%), a significant difference relative to cisplatin alone (p < 0.05). The daily administration of S-1 combined with low-dose cisplatin induced tumor regression with a low toxicity.

[Experimental studies on the antitumor effect of oral antitumor agents on gynecological malignant tumors].

In order to evaluate the antitumor effect of oral antitumor agents on gynecological malignant tumors, experimental studies were carried out using nude mice which had received implants of human endometrial carcinoma. The agents used for the study were tegafur (T) and UFT, and their effects on inhibiting tumor growth, and on preventing tumors from implanting or recurring were investigated in mice in continuous long-term administrations. The results were as follows: As to the inhibitory effect on the tumor growth, while both T and UFT had no inhibitory effect on large to medium tumors, both were mildly effective on small tumors having a diameter of 2-3 mm (Inhibition Rate (IR): T-60.0%, UFT-71.0%), however, the no effect great enough to reduce the tumor size was recognized with either agent. The implantation rates of tumor under the administration of T and UFT were 80.0% and 70.0% respectively, indicating no significant differences from the control (90.0%) and either agent, however, UFT was judged to have the effect of preventing tumors from implanting to a certain extent. The recurrence rates for tumor under the administration of T and UFT were 30.0% (6/20) in both cases, which was significantly lower than the control (70.0%) (p less than 0.05). Both agents were evaluated as useful for preventing tumors from recurring. These findings, indicated that while the maintenance therapy of an oral antitumor agent has no effect on macroscopic tumors, a fairly good effect is expected on microscopic tumors, especially on the prevention of tumor recurrence.