We evaluated the anticancer effect of UFT, which is composed of 1-(2-tetrahydrofuryl)-5-fluorouracil (Tegafur) and uracil in a molar ratio of 1:4, for prostatic carcinoma (DU-145) in nude mice, and the effect of 5-fluorouracil (5-FU) in vitro. Tumor growth of DU-145 in nude mice was inhibited in the group administered UFT (20 mg/kg), but was not in the Tegafur (100 mg/kg) group in comparison with the control group. The concentration of 5-FU in the tumor reached higher levels in the group administered UFT in comparison with the Tegafur group. Also, DU-145 cells were inhibited by about 70% in 4 gamma concentration of 5-FU compared with the control. These data suggest the clinical usefulness of UFT for prostatic carcinoma.

Patients with meningeal carcinomatosis often evolve signs of impairment in higher mental function. Yet, common findings of histological observation are only a sheet of tumor cells on the cortical surface, and no intracerebral mass are noted. To elucidate mechanism of mental disturbances in meningeal carcinomatosis, local cerebral blood flow and glucose metabolism were evaluated in a model of experimental meningeal carcinomatosis. Viable cells (1 X 10(4) of Walker 256 tumor were inoculated into cisterna magna of Wistar rats. Animals were used for autoradiographic study at 1 to 12 days after tumor inoculation. Local cerebral glucose utilization (LCGU) and local cerebral blood flow (LCBF) were measured with quantitative autoradiographic technique using 14C-iodoantipyrine and 14C-deoxyglucose as a tracer, respectively. In the early stage of tumor growth (1 to 3 days after tumor inoculation), reduction of LCGU was averaged to be 31% in the cerebral cortex and 28% in the deep structures, whereas reduction of LCBF was 28% in cerebral cortex and 19% in deep structures on average. In the late stage of tumor growth (4 to 12 days after tumor inoculation), average reduction of LCGU was 57% in the cerebral cortex and 47% in the deep structures. On the other hand, reduction of LCBF was averaged to be 42% in the cerebral cortex and 38% in the deep structures in the late stage of the disease. Reduction of LCGU and LCBF was especially evident in the sensory cortices such as parietal cortex, visual cortex and auditory cortex, and in the auditory centers of the brain stem such as medial geniculate body and inferior colliculus.(ABSTRACT TRUNCATED AT 250 WORDS)

We have developed a simple in vitro chemosensitivity test for breast cancer. Tumor tissues were chopped finely with razor blade. The cell clumps were pounced into tissue culture medium, which contained a specified level of concentration of anticancer drugs, and incubated at 37 degrees C for four to eight hours. Nine to 10 kinds of drugs were tested on each specimen. After incubation, the clumps were pumped down. The cells were smeared and stained with Giemsa for microscopic examination. The individual tumors showed different sensitivities towards various drugs, and the typical morphological changes observed in their nuclei; were karyorrhexis and karyopyknosis.

Prognostic indicators in the clinical study were discussed at the cellular level in relation to the number of tumor stem cell, the rate of repopulation during the treatment course and cellular radio-chemosensitivity. The number of tumor stem cells seems to correlate to tumor volume in the narrowly defined tumor type, but may not in the mixed group of tumor types. Thymidine or BUdR labeling index may be an useful indicator of rate of repopulation and also of tumor aggressiveness. Cellular radio-chemosensitivity varies not only among tumor types but also among subpopulations within a tumor. Further investigations of tumor stem cell assay in the response to radio-chemotherapy using fresh tumor specimens from patients are certainly required before the assay methods are established.

A new ovarian cancer cell line has been established from the dispersed cells taken from a heterotransplanted tumor at the 6th passage in nude mice which had been serially transplanted with a primary lesion of undifferentiated carcinoma (FIGO) of the ovary. Selection of cancerous epithelioid cells was completed by the 4th passage by means of the colonial cloning method. The cell line designated TYK-nu was subcultured serially in Eagle's MEM with 10% FCS more than 100 times over 31 months at March, 1986 and was observed to produce a tumor on implantation into nude mice histologically similar to the original tumor. These cells form a monolayer in a pavement-like arrangement with polygonal cells including giant cells and reveal a lack of contact inhibition. PAS positive substance can be seen in the cytoplasm. Desmosome structure, well-developed cell organelles and glycogen granules can be found by electron microscopy. The population doubling time was about 37 hours and the plating efficiency was 13-17%. All cells were seen to be of the human karyotype on chromosomal analysis and the number of chromosome in the majority of cells was hyperdiploidy with a mode of 56 at the 6th and 84th passages. A submetacentric marker chromosome was present. Using in vitro colony assay, TYK-nu was studied for drug sensitivity to cisplatin, adriamycin, vincristine, 5-fluorouracil and etoposide, and found to be sensitive to cisplatin.

In order to conduct a fundamental investigation of the effect of UFT on malignant tumors, biological experiments were conducted. UFT, 300 mg/day, starting one week prior to surgery, was administered in 12 cases of ovarian carcinoma. During the operation, 5-FU concentrations in serum, tumor tissues and adjacent normal tissues were measured. The results were as follows: 0.009 +/- 0.005 micrograms/ml in serum; 0.157 +/- 0.214 micrograms/g in tumor tissues, and 0.042 +/- 0.028 micrograms/g in adjacent normal tissues. Based upon these values, the plating efficiency of cultured tumor cell lines was measured in the presence of 5-FU in vitro. With 5-FU concentrations of 0.01 micrograms/ml, no sign of restriction in plating efficiency was observed. Restriction was initially observed at 0.1 microgram/ml, and became more pronounced at 1.0 microgram/ml. Furthermore, experiments using a uterine cervical carcinoma cell line (SKG-3) indicated that restriction of the plating efficiency was enhanced, not only by the 5-FU concentration but also by lapse of time.

The cytotoxic and cytokinetic effects of prostaglandin (PG)D2 on human and rat glioma cells were studied in vitro, and the morphological changes occurring in glioma cells following PGD2 treatment were investigated by light and electron microscopy. The cytotoxic effect was evaluated by both colony formation assay and cell growth inhibition. The cytokinetic effect was analyzed by DNA histogram using a flow cytometer. It was found that PGD2 had a dose-dependent cytotoxic effect on the glioma cells and that rat C6 cells were less sensitive to PGD2 than human KY cells. Within 24h after treatment of KY cells with PGD2, a time-dependent cytotoxic effect was also observed. However, the effect of PGD2 on glioma cells was reversible at lower concentration. Investigation of KY cells treated with 2.5 micrograms/ml of PGD2 revealed that the cells in S and G2 + M phases gradually decreased in number and subsequently almost all cells were accumulated in the G0 + G1 phase 12 h later. However, no chronological change of the DNA histogram was obvious in the cells treated with a relatively high concentration of PGD2 (10 micrograms/ml). On the other hand, the treated cells showed more severe morphological changes at a higher concentration of PGD2. Glioma cells treated with PGD2 became round with cytoplasmic vacuolization and blebbing. Thus, PGD2 appears to be useful as an adjuvant chemotherapeutic agent for malignant glioma.

To improve the postoperative survival rate of patients with cervical cancer, those with clinical stage Ib or above were treated with adjuvant chemotherapy (oral Tegafur). The drug sensitivity of cultured cervical epidermoid cancer cells was tested with 5-fluorouracil (5-FU), an active derivative of Tegafur. The cumulative rate of recurrence of the group treated with adjuvant chemotherapy was 28.4% (19/67 cases), significantly lower than that of the untreated control group 69.8% (44/63 cases) (p less than 0.01). The rate of recurrence for the two groups was evaluated with Cox's regression models. The rate of recurrence of the treated group was about 50% that of the untreated group. The drug sensitivity of the cultured cancer cells was investigated with a colony forming assay, and a dose-response curve was obtained for the time-dependent anticancer drug. The inhibition of DNA synthesis peaked after 24 to 72 hours of incubation with 5-FU at 0.1 to 0.5 micrograms/ml, but the peak appeared in 4 to 8 hours at 1.0 to 10.0 micrograms/ml. Morphologic changes occurred after 192 hours of incubation at 0.1 microgram/ml. Investigation of the drug sensitivity by cell kinetics disclosed prolongation of the cell cycle after 144 hours at 0.1 microgram/ml and inhibition of cell cycle progression after 48 hours at 10.0 micrograms/ml. Thus, adjuvant chemotherapy with Tegafur reduces the rate of recurrence to about 50% in postoperative patients with cervical cancer. This finding was also supported by an experimental study.

Effects of prostaglandin F2 alpha, E2, D2 and J2 on the DNA and RNA contents of a human endometrial cancer cell lines (SNG and Ishikawa) were studied using flow cytometry. Cytotoxic effects of various prostaglandins on SNG and Ishikawa cell lines were examined and PG J2 and PG D2 were found most active. Among other prostaglandins PG E2 showed a comparable inhibitory activity to cellular growth but PG F2 alpha didn't. In SNG and Ishikawa cell lines after RNase treatment, PG J2, PG D2 and PG E2 caused a decrease of the S-phase and G2 + M-phase cell population in cell cycle. On the other hand, PG F2 alpha caused a increase of the S-phase cell population in cell cycle PG J2, PG D2 and PG E2 after DNase treatment caused a decrease of the relative RNA content in both of cell lines. On the other hand, PG F2 alpha caused a increase of the relative RNA content. It is a noteworthy that PG J2 and PG D2 were remarkably recognized delay of doubling time and decrease of survival fraction under the time and dose dependence. These effects occur not only by direct lethal influence of the prostaglandins, but also by substantially inhibit RNA and DNA synthesis with a delay of the cell cycle. These results might be suggested a role for prostaglandin J2 and D2 in the regulation of growth of endometrial adenocarcinoma cells.

In vitro chemosensitivity was evaluated by succinate dehydrogenase inhibition (SDI) test in 94 human tumors including 59 gastric cancers, 27 colo-rectal cancers and 8 malignant lymphomas. Tumor fragments were exposed to 12 kinds of antitumor drugs at ten times peak plasma concentration. Evaluable rates were 86/94 (91%) for all cases, 56/59 (95%) for gastric cancers, 22/27 (81%) for colo-rectal cancers and 8/8 (100%) for malignant lymphomas. The mean of SD activity was decreased to 48% of that of control cells with aclacinomycin, 49% with carboquone, 53% with actinomycin D, 54% with mitomycin C and 54% with daunomycin for gastric cancers, 59% with adriamycin for colo-rectal cancers and 33% with cyclophosphamide (40487 S), and 33% with actinomycin D, 37% with vinblastine and 39% with adriamycin for malignant lymphomas. When the SD activity was reduced to below 50% by antitumor drugs, the chemosensitivity was defined as positive. The antitumor drugs which had a higher chemosensitive-positive rate were aclacinomycin, carboquone and mitomycin C for gastric cancers, adriamycin for colo-rectal cancers and 40487 S, daunomycin and vinblastine for malignant lymphomas. Our results suggest that the origin of a tumor is a critical factor in its chemosensitivity.

A 58-year-old man recognized hoarseness and dysarthria followed by weakness of the left upper extremity. Examination five months later disclosed dementia which was manifested dominantly by changes in personality and behavior, but also by symptoms of amyotrophic lateral sclerosis. He became progressively weak, and his neck became rigid and extended for two months. He expired due to respiratory failure at the age of 60. At autopsy, the brain weighed 1120 g with atrophy of the temporal lobes. Microscopic examination revealed marked diminution of Betz cells with astrocytic proliferation in the motor cortex. There was a mild, localized spongy state in the upper layer in the frontal and temporal cortices. There were very few neurofibrillary changes and senile plaques, and no Pick's argentophilic bodies. Fibrillary gliosis was found in the white matter of the temporal lobes, external segment of the globus pallidus and the amygdaloid nucleus. The substantia nigra showed depletion of pigmented cells, free melanin pigment and reactive astrocytosis. A diminished number of motor neurons in the brain stem and spinal cord accompanied astrocytic gliosis, while the remaining cell contained many Bunina bodies. The pyramidal tracts showed mild degeneration bilaterally below the pyramis in the medulla. There are a number of cases in the literature whose pictures consist of amyotrophic lateral sclerosis, dementia and/or extrapyramidal symptoms. This case is identical to those cases. But in this case, the clinical and pathological features of amyotrophic lateral sclerosis are more dominant than in other cases.