[Blood concentrations of futraful, uracil and 5-fluorouracil (5-FU) after UFT administration in the various reconstructions after gastrectomy. Saitama UFT Research Group].

The study was undertaken in the total of 58 gastric cancer patients among which 17 of Billroth (BI), 14 of Billroth II (B II) anastomosis after subtotal gastrectomy, and 7 of jejunal interposition, 9 of double tract and 11 of Roux en Y anastomosis after total gastrectomy were included. Blood samples were taken before 200 mg of per oral UFT administration and after 1, 2, 3, 5 and 7hrs. consecutively. The blood Futraful (FT) level in the total gastrectomy groups reached peak concentration within 1hr and kept in relatively high level during the observation period of 7hrs. The time to maximum FT concentration delayed in almost of B I and a few of B II patients. The concentration curves of uracil (URA) and 5-FU were similar in shape, revealing steep increase and decrease except B I anastomosis which showed gentle course. The plotted maximum concentrations of URA and 5-FU in the every type of reconstruction showed a significant correlation in the regression line. In the analysis of AUC, URA/FT was under 10%, suggesting the longer retention of the unmetabolite type of FT and early disappearance of URA. The ratio of 5-FU/FT was indifferent in each reconstruction. 5-FU/URA was higher in subtotal rather than total gastrectomy groups. From the data obtained, blood concentration of 5-FU after UFT administration was considered to depend on the emptying status in the gastrectomies. And moreover, it depended on blood URA level, since FT from which 5-FU was derived, was kept still sufficiently remained during observation period.

[Experimental combined chemo- and endocrine therapy with UFT and tamoxifen in human breast carcinoma xenografts serially transplanted into nude mice].

We have investigated the experimental combined chemo- and endocrine therapy of UFT and tamoxifen (TAM) on two human breast carcinoma xenografts, R-27 and Br-10 with estrogen receptors (ER) serially transplanted into nude mice. When sc inoculated tumor started the exponential growth, the treatments were initiated in four groups which were control, UFT 20 mg/kg (as tegafur) po daily for 18 times, TAM 5 mg/kg im twice a week for 6 times and UFT + TAM groups. The antitumor activity of the agents were assessed by the growth curves, the lowest T/C ratios of the relative mean tumor weight and the actual tumor weights at the end of the experiments. TAM alone was effective on both R-27 and ineffective on Br-10, while UFT alone was ineffective on R-27 and Br-10. The combination antitumor activity was observed in R-27 but not in Br-10. When 5 mg of TAM per kg and 20 mg of UFT per kg as tegafur was administered daily po for 2 wk, there were no statistically significant differences between the concentration of 5-FU in UFT alone and UFT + TAM groups for the two strains. By the assay of ER and progesterone receptors using the same specimen, it was observed that ER was stable by the treatment of UFT, while ER was suppressed by the treatment of TAM in both tumor strains. In addition, this suppression of ER by TAM alone was enhanced by the combined treatment with UFT in both the strains.(ABSTRACT TRUNCATED AT 250 WORDS)

Antitumor activity and pharmacokinetics of a morpholino-anthracycline derivative (KRN8602) against human breast carcinoma xenografts serially transplanted into nude mice.

The antitumor activity and pharmacokinetics of (7R, 8S, 10S)-10-((3-deamino- 3-(4-morpholino)-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy)-8- ethyl- 7,8,9,10-tetrahydro-1,6,7,8,11-pentahydroxy-5,12-naphthacenedione hydrochloride (KRN8602) were evaluated using five human breast carcinoma xenografts in nude mice. The maximum non-toxic dose of KRN8602 was 2 mg/kg by q4d x 3 intraperitoneal and peroral administration. KRN8602 showed significant antitumor activity against MX-1, which is less sensitive to adriamycin, with the chemotherapeutic indices of 13.0 for po administration and 9.5 for ip injection. Although KRN8602 also inhibited the growth of T-61 significantly, the antitumor activity of this agent against the other three breast carcinoma xenografts was limited. To elucidate this discrepancy, pharmacokinetic analysis and MTT assay were conducted using the KRN8602-sensitive MX-1 and KRN8602-insensitive R-27. While no differences were observed in the area under the curve and the peak concentration of KRN8602 for each tumor, a difference in the sensitivity of the tumor strains was obvious in MTT assay. The efficacy of this agent seemed to depend on the sensitivity of each type of tumor cell rather than the concentration of agent in tumor tissues. If it were possible to select patients with sensitive tumor cells to this agent by the MTT assay, the phase II trial might be completed within a short period by reducing the number of studied patients.

Changes in the hormone receptors of human breast carcinoma xenografts in nude mice by treatment with cytotoxic agents.

We examined the effect of chemotherapeutic agents on the estrogen receptors (ER) of breast carcinomas in vivo using human breast carcinoma strains (Br-10, T-61) serially transplanted into nude mice. When the tumor size reached approximately 1 X 1 X 1 cm, mitomycin C (MMC) at doses of 1, 2 and 4.5 mg/kg and cyclophosphamide (CPA) at a dose of 120 mg/kg, were administered once intraperitoneally, and the ERs of the tumors were measured sequentially by the dextran-coated charcoal method. Four days after the MMC administration at above doses, the binding sites of ER in Br-10 were not reduced and binding affinity was not affected. When the changes in ER content with time after the treatment with 4.5 mg/kg MMC and 120 mg/kg CPA were investigated, the ER content was found to be stable until 4 days after the treatment with both drugs, although the growth of T-61 had been significantly inhibited by the drugs. From these findings, it seems reasonable to initiate chemotherapy before endocrine therapy, since the chemotherapeutic agents did not reduce the ER content of the breast cancer strains.

Immunohistochemical analysis of mesocolic lymph node cells in human colorectal cancer.

Localization of lymphocyte subsets and macrophages in the mesocolic lymph node of the colorectal cancer and their distribution among the paracolic, intermediate, and main nodes were studied quantitatively by means of immunohistochemical staining with monoclonal antibodies. In all of the three lymph node groups, in the paracortex, helper/inducer T cells were more numerous than suppressor/cytotoxic T cells. The number of whole T cells in the paracortex diminished with increasing proximity to the primary tumor. In the three lymph node groups, no significant difference was found regarding the ratio of the cell number among suppressor/cytotoxic T cells, natural killer cells, and macrophages. Lymphocytes in the paracortex of lymph node had a positive correlation to lymphocytes in the peritumoral stroma and intratumoral fields. These data neither suggest the presence of a powerful immunological reaction in the mesocolic lymph node nor support the concept of conservation of uninvolved regional lymph nodes in the surgery of the colorectal cancer.

[Hormone independent murine carcinoma BX-1 spontaneously arising from nude mouse bearing Br-10, a hormone dependent human breast carcinoma strain].

BX-1, an adenocarcinoma spontaneously arising from nude mouse bearing Br-10, a human breast carcinoma strain was characterized. And the purification of a hormone independent murine carcinoma strain, BX-1 was found in August 1986 in three institutes where a hormone dependent transplantable human breast carcinoma cell line Br-10 has been serially passaged. The histological features of BX-1 were different from any other strains which were maintained in these three institutes. Estrogen receptor of BX-1 was negative and no estrogen dependency was observed while Br-10 was the receptor positive and the growth of Br-10 was dependent on estrogen. Although the graft of BX-1 into the thymus intact littermates was rejected, the chromosomal analysis revealed only murine chromosomes for BX-1, while both of human and murine chromosomes were detected in Br-10 tumor. By incubating Br-10 tumor in untreated female nude mice for 2 months and stimulating the growth of the tumor by exogenous estradiol, the purification of Br-10 from BX-1 could be achieved. Whereas the stability of human tumor xenografts in nude mice is confirmed, the spontaneously arising murine tumor from nude mice bearing human tumor xenografts should be considered for the experiments.

[2 cases of bullous pemphigoid and Bowen's disease associated with esophageal cancer].

There are many published reports on the combination of malignant tumors of the digestive tract and various skin diseases. To date, 8 cases with combined bullous pemphigoid and malignant tumor, or Bowen's disease and malignant tumor, have been reported in Japan. In only 2 cases was the esophageal cancer combined with skin disease. The pathophysiological relationship between skin diseases and malignant tumors of the digestive tract remains unknown.