Role of BK Channels in Murine Carotid Body Neural Responses in vivo.

The aim of this study was to explore the role of BK channels in the hypoxic sensitivity of the in vivo murine carotid body (CB). Four strains of mice (DBA/2J, A/J, BKα1 knockout and BKα1 wild type - FVB background) were used. The mice were anesthetized, paralyzed and mechanically ventilated (PaCO(2) ~ 35 mmHg, PO(2) > 300 mmHg). We measured carotid sinus nerve (CSN) activity during three gas challenges (F(I)O(2): 0.21, 0.15 and 0.10). CSN activity was analyzed with time-variant spectral analysis with frequency domain conversion (Fast Fourier Transforms). Afferent CSN activity increased with lowering F(I)O(2) in the DBA/2J, BKKO and BKWT mice with the most robust response in 600-800 frequencies. No substantial changes were observed in the A/J mice. Although maximal neural output was similar between the BKKO and BKWT mice, the BKWT had a higher early response compared to BKKO. Thus, BK channels may play a role in the initial response of the CB to hypoxia. The contribution of BKß subunits or the importance of frequency specific responses was unable to be determined by the current study.

Association of genetic variants for susceptibility to obesity with type 2 diabetes in Japanese individuals.

AIMS/HYPOTHESIS: In populations of East Asian descent, we performed a replication study of loci previously identified in populations of European descent as being associated with obesity measures such as BMI and type 2 diabetes. METHODS: We genotyped 14 single nucleotide polymorphisms (SNPs) from 13 candidate loci that had previously been identified by genome-wide association meta-analyses for obesity measures in Europeans. Genotyping was done in 18,264 participants from two general Japanese populations. For SNPs showing an obesity association in Japanese individuals, we further examined diabetes associations in up to 6,781 cases and 7,307 controls from a subset of the original, as well as from additional populations. RESULTS: Significant obesity associations (p < 0.1 two-tailed, concordant direction with previous reports) were replicated for 11 SNPs from the following ten loci in Japanese participants: SEC16B, TMEM18, GNPDA2, BDNF, MTCH2, BCDIN3D-FAIM2, SH2B1-ATP2A1, FTO, MC4R and KCTD15. The strongest effect was observed at TMEM18 rs4854344 (p = 7.1 × 10(-7) for BMI). Among the 11 SNPs showing significant obesity association, six were also associated with diabetes (OR 1.05-1.17; p = 0.04-2.4 × 10(-7)) after adjustment for BMI in the Japanese. When meta-analysed with data from the previous reports, the BMI-adjusted diabetes association was found to be highly significant for the FTO locus in East Asians (OR 1.13; 95% CI 1.09-1.18; p = 7.8 × 10(-10)) with substantial inter-ethnic heterogeneity (p = 0.003). CONCLUSIONS/INTERPRETATION: We confirmed that ten candidate loci are associated with obesity measures in the general Japanese populations. Six (of ten) loci exert diabetogenic effects in the Japanese, although relatively modest in size, and independently of increased adiposity.

Common variants at the GCK, GCKR, G6PC2-ABCB11 and MTNR1B loci are associated with fasting glucose in two Asian populations.

AIMS/HYPOTHESIS: To test fasting glucose association at four loci recently identified or verified by genome-wide association (GWA) studies of European populations, we performed a replication study in two Asian populations. METHODS: We genotyped five common variants previously reported in Europeans: rs1799884 (GCK), rs780094 (GCKR), rs560887 (G6PC2-ABCB11) and both rs1387153 and rs10830963 (MTNR1B) in the general Japanese (n = 4,813) and Sri Lankan (n = 2,319) populations. To identify novel variants, we further examined genetic associations near each locus by using GWA scan data on 776 non-diabetic Japanese samples. RESULTS: Fasting glucose association was replicated for the five single nucleotide polymorphisms (SNPs) at p < 0.05 (one-tailed test) in South Asians (Sri Lankan) as well as in East Asians (Japanese). In fine-mapping by GWA scan data, we identified in the G6PC2-ABCB11 region a novel SNP, rs3755157, with significant association in Japanese (p = 2.6 x 10(-8)) and Sri Lankan (p = 0.001) populations. The strength of association was more prominent at rs3755157 than that of the original SNP rs560887, with allelic heterogeneity detected between the SNPs. On analysing the cumulative effect of associated SNPs, we found the per-allele gradients (beta = 0.055 and 0.069 mmol/l in Japanese and Sri Lankans, respectively) to be almost equivalent to those reported in Europeans. CONCLUSIONS/INTERPRETATION: Fasting glucose association at four tested loci was proven to be replicable across ethnic groups. Despite this overall consistency, ethnic diversity in the pattern and strength of linkage disequilibrium certainly exists and can help to appreciably reduce potential causal variants after GWA studies.

Differential effects of prenatal stress on the morphological maturation of hippocampal neurons.

The present study was designed to clarify an intensity-dependent effect of prenatal stress on the morphological development of hippocampal neurons in rats. In addition, the involvement of receptors for glucocorticoids, i.e. mineralocorticoid receptors and glucocorticoid receptors, in stress-induced changes in the morphology of hippocampal neurons was examined by an in vitro pharmacological approach. The effects of mild prenatal stress on neurogenesis and long-term potentiation in the hippocampus were also investigated in adult offspring. Prenatal stress affected the morphological development of the hippocampus in an intensity-dependent manner. Short-lasting, mild prenatal stress enhanced neonatal neurogenesis and differentiation of processes of hippocampal neurons, whereas long-lasting, severe stress impaired their morphology. Mineralocorticoid receptor was found to mediate enhancement of neurogenesis and differentiation of processes of cultured hippocampal neurons. In contrast, glucocorticoid receptor was involved in the suppression of their morphology. Short-lasting, mild prenatal stress, which has previously been shown to enhance learning performance in adult offspring, facilitated neurogenesis and long-term potentiation in the adult hippocampus. These findings suggest that prenatal stress has enhancing and suppressing effects on the development of hippocampal neurons depending on intensity, and that mineralocorticoid receptors and glucocorticoid receptors contribute to stress-induced morphological changes.

Antitumor activity of 1 M tegafur-0.4 M 5-chloro-2,4-dihydroxypyridine-1 M potassium oxonate (S-1) against human colon carcinoma orthotopically implanted into nude rats.

The purpose of this study was to establish a nude rat orthotopic (organ-specific) human colorectal cancer model as an in vivo secondary screen for general evaluation of new anticancer agents against colorectal cancer and to evaluate practically the antitumor activity of 1 M tegafur-0.4 M 5-chloro-2,4-dihydroxypyridine-1 M potassium oxonate (S-1), a new p.o. fluoropyrimidine, in comparison to 1 M tegafur-4 M uracil [(UFT) effective on colorectal tumor in clinical]. After implantation of KM12C, a human colorectal cancer cell line, into the subserosal layer of the colon as a single-cell suspension, extensive local tumor growth and invasion to both the mucosal and the serosal sides were observed in all rats. Metastatic foci were also formed in both lymph nodes and lungs following local tumor growth in all of them. Using this method, an equitoxic dose of S-1 (15 mg/kg/day) and UFT (30 mg/kg/day) was administered p.o. for 14 consecutive days from 7 days after tumor cell implantation. S-1 showed a higher tumor growth inhibition than UFT did [S-1, 57% (significantly different from the tumor weight of the untreated group at P < 0.05) and UFT, 18% (P > 0.05)]. When both drugs were administered to nude rats bearing KM12C injected into the cecal wall for 28 consecutive days at equitoxic doses, the mean survival in the S-1 group was 16 days longer than that in the untreated group (P < 0.01) but that in the UFT group was only 8 days longer (P > 0.05). After the administration of an equitoxic dose of both drugs, S-1 gave the higher levels than UFT in various pharmacokinetic parameters as follows: area under the curve 0-24 h of 5-fluorouracil in plasma (3.5-fold), area under the curve 0-24 h of 5-fluorouracil incorporated into RNA in the tumor (1.3-fold), and thymidylate synthase inhibition rate (percentage) in the tumor (about 20%). Collectively, these findings suggested that this orthotopic human colorectal tumor model in nude rats is useful to evaluate the clinical therapeutic efficacy of drugs or therapies for colorectal cancer, and that S-1 had a higher therapeutic effect on human colorectal tumor than UFT did.

Postsurgical oral administration of uracil and tegafur inhibits progression of micrometastasis of human breast cancer cells in nude mice.

We recently established a metastasis model in nude mice using the MKL-4 cell line, a contransfectant of the MCF-7 human breast cancer cell line with fgf-4 and lacZ in which micrometastases in several organs can be quantitatively observed. First, to develop a new postsurgical metastasis model, we investigated the timing of occurrence of micrometastasis and the influence of tumor removal on the progression of micrometastasis in this model. Micrometastases into lymph nodes and lungs were detected 3 weeks after the cell injections. Tumor removal 3 weeks after the injections significantly enhanced the progression of micrometastasis into lymph nodes and bone. Second, to study the effect of a mixed compound, UFT (a molar ratio of uracil:tegafur of 4:1), which has been widely used in the postsurgical adjuvant setting in Japan, 15 or 20 mg/kg UFT were administered p.o. for 4 weeks to tumor-bearing mice or to mice in which transplanted tumors were resected 3 weeks after the injections. Either dose of UFT significantly inhibited the tumor growth as well as the progression of micrometastasis into lymph nodes, lungs, liver, and brain. In addition, enhanced progression of micrometastasis in all explored organs by the tumor removal was significantly inhibited by the administration of either dose of UFT. In conclusion, this new postsurgical metastasis model may be useful for evaluating the efficacy of agents used in the postoperative adjuvant setting. UFT may be an effective drug for inhibiting the progression of micrometastasis after surgery.

Skin granuloma formation in mice immunosuppressed by cyclosporine.

Granulomatous tissue reactions appear in athymic mouse skin, indicating that initiation of granuloma formation may be T-cell independent. To further evaluate the relationships between granuloma formation and T-cell function, we treated euthymic BALB/c mice with cyclosporine (Cs), a potent immunosuppressive drug, injected intramuscularly (150 mg/kg/day) 5 times a week. Hepatic granulomas were isolated from mice with schistosomiasis and transplanted into the skin of mice treated with Cs for 2 weeks. Cyclosporine injection was continued for 3 additional weeks. Blood levels of the drug increased during treatment (489 ng/ml at 2 weeks and 822 ng/ml at 5 weeks). Morphologically identical granulomas developed in both treated and untreated mice. Examination for T-cell functions showed that by the end of 2 weeks treatment, concanavalin A, phytohemagglutinin responses, and IL-2 activity were markedly depressed, and IL-2 receptor expression was not detected in either lymph nodes or spleen of the Cs-treated mice; however, after hepatic granuloma graft, T-cell functions in regional lymph nodes, but not in spleen, as well as peripheral blood eosinophilia were stimulated in Cs-treated mice. These data strongly suggest that intact T-cell activity is not essential for the initiation of granuloma formation. In addition, granuloma grafts appear to stimulate Cs-resistant T-cell activation locally, which amplifies and organizes the granulomatous response.

The effect of quercetin on cell cycle progression and growth of human gastric cancer cells.

Quercetin, a flavonoid, is found in many plants, including edible fruits and vegetables. We examined the effects on cell growth of human malignant cells derived from the gastrointestinal tract and on cell cycle progression. Quercetin markedly inhibited the growth of human gastric cancer cells and the IC50 value was 32-55 microM. DNA synthesis was suppressed to 14% of the control level by the treatment with 70 microM quercetin for 2 days. Furthermore, quercetin blocked cell progression from the G1 to the S phase.

Enhancement of the antitumour activity of 5-fluorouracil (5-FU) by inhibiting dihydropyrimidine dehydrogenase activity (DPD) using 5-chloro-2,4-dihydroxypyridine (CDHP) in human tumour cells.

The purpose of this study was to evaluate the use of 5-chloro-2,4-dihydroxypyridine (CDHP), a potent inhibitor of dihydropyrimidine dehydrogenase (DPD), to enhance the antitumour activity of the fluoropyrimidines. In an in vitro study, CDHP did not influence cell proliferation by itself. However, CDHP did inhibit 5-fluorouracil (5-FU) degradation and enhanced 5-FU cytotoxicity in a concentration-dependent manner in two human tumour cell lines (MIAPaCa-2 and HuTu80) with relatively high basal DPD activity. CDHP exhibited a maximum effect at a molar ratio (CDHP:5-FU) of more than 0.2. However, CDHP did not have any effect on 5-FU cytotoxicity in the CAL27 tumour cell line, which has a relatively low basal DPD activity, even at concentrations where the DPD activity is almost completely inhibited. In an in vivo study, the maximal tolerable doses (MTD) of tegafur (FT) and a combination of FT and CDHP at a molar ratio of 1:0.4 (FT/CDHP) for nude mice were determined by oral administration for 14 consecutive days. After a single oral administration of either FT or FT/CDHP at the MTD, the 5-FU serum concentration-time profiles were almost the same for both treatment strategies. When nude mice bearing subcutaneous (s.c.) MIAPaCa-2 cells were treated with either FT or FT/CDHP at the MTD, the FT/CDHP treatment showed a significantly higher antitumour effect than the FT treatment (tumour growth inhibition: FT/CDHP, 51+/-12%; FT, 21+/-25%; P<0.05). However, the host-body weight suppression induced by FT/CDHP and FT was equivalent. These findings suggest that the combination of fluoropyrimidine and CDHP for the treatment of tumours with a high basal DPD elicits a greater antitumour effect than treatment with fluoropyrimidines alone and we suggest that CDHP inhibits the degradation of 5-FU in the tumour.

Thymidylate synthase (TS) and ribonucleotide reductase (RNR) may be involved in acquired resistance to 5-fluorouracil (5-FU) in human cancer xenografts in vivo.

A human tumour sub-line resistant to 5-fluorouracil (5-FU) was established by once a day and every 5, with at least 50 administrations of 5-FU to KM12C human colorectal xenografts in nude mice. KM12C tumours treated with 5-FU showed less sensitivity to 5-FU with an inhibition rate (IR) of 7.9%, while non-treated tumours were highly sensitive to 5-FU with an IR of 81.8%. To clarify the mechanism of 5-FU-resistance, the activities of various enzymes and gene expressions involved in the metabolism of 5-FU in both parental and 5-FU-treated KM12C tumours were measured. A 2- to 3-fold increase in thymidylate synthase (TS) activity and 4- to 5-fold decrease in ribonucleotide reductase (RNR) activity were observed in 5-FU-resistant KM12C tumours, while the activities of orotate phosphoribosyltransferase (OPRT) thymidine and uridine phosphorylases (TP,UP) and thymidine kinase (TK) were not markedly changed as a consequence of repeated treatment of KM12C tumours with 5-FU. The expression of TS mRNA was also amplified in accordance with the increased TS activity in a 5-FU-treated tumour sub-line (KM12C/5-FU) compared with that in parental tumours, but changed expressions of both RNR-R1 and RNA-R2 mRNA could not be detected in the 5-FU-resistant tumour sub-line compared with the parental tumours, suggesting possible post-transcriptional regulation of RNR. Moreover, RNR, in addition to TS and OPRT, seemed to be related to the inherent insensitivity to 5-FU in human cancer xenografts. From these results, it may be concluded that RNR activity is one of the acquired or inherent resistant factors, including TS, to 5-FU in human cancer xenografts in vivo.

Mild prenatal stress enhances learning performance in the non-adopted rat offspring.

The present study was designed to investigate whether mild stress during pregnancy affects offspring behaviors, including learning performance. Prenatal stress was induced by short-lasting, mild restraint stress, which had previously been shown to facilitate the morphological development of fetal brain neurons. Adult offspring whose dams had been restrained in a small cage for 30min daily from gestation day 15 to 17 showed enhanced active avoidance and radial maze learning performance. In addition, the prenatally stressed rats showed weaker emotional responses than unstressed control, as indicated by decreases both in ambulation upon initial exposure to an open field and in Fos expression in the amygdala induced by physical stress. The observed effects of prenatal stress on learning performance and emotional behavior were attenuated by foster rearing by unstressed dams. Fos expression in the hypothalamic paraventricular nucleus following physical stress and corticosterone secretion during physical and psychological stress did not differ between the prenatally stressed and unstressed control rats. From these results we suggest that mild prenatal stress facilitates learning performance in the adult offspring. The enhancement of learning performance appears to be accompanied by reduced emotionality, but not by any apparent alterations in hypothalamic-pituitary-adrenal responses. In addition, the observation of differential behaviors in the adopted and non-adopted animals supports the notion that the postnatal environment modifies the behavioral effects of prenatal stress.

Materno-fetal coordination of stress-induced Fos expression in the hypothalamic paraventricular nucleus during pregnancy.

This study investigates whether maternal stress during pregnancy induces maternal and fetal hypothalamic paraventricular nucleus (PVN) neuronal activation and the effects of maternal stress on fetal hypothalamic and PVN brain-derived neurotrophic factor (BDNF) expression. Pregnant rats were exposed to three types of maternal stress with varying severity (restraint, forced walking and immobilization) for 30 min on gestational day 21. Severity of stress was assessed by measurement of maternal plasma corticosterone 30 min following the stimulus. Maternal plasma corticosterone increased in each stress response group (immobilization>forced walking>restraint). Further, the expression of Fos protein, a marker of neuronal activation, increased in the fetal and maternal PVN in direct relation to the severity of stress treatments. Forced walking and immobilized stress, but not restraint stress, significantly increased BDNF expression in the fetal hypothalamus.These findings suggest that the fetal hypothalamic-pituitary-adrenal (HPA) response following maternal stress mirrors maternal HPA activation. In addition, BDNF may play a role in protecting fetal brain neurons from damage caused by severe stress.

Prolongation of survival period and improvement of cancer cachexia by long-term administration of UFT.

We assayed the antitumoral and anticachectic activity of an oral fluoropyrimidine, UFT using the Colon-26-bearing murine cachexia model in terms of the survival period and parameters corresponding to clinical symptoms. Tumor growth was inhibited by UFT dose-dependently at the dose range of 12.5-25.0 mg/kg per day. Although UFT did not show significant growth inhibition at 15.0 and 12.5 mg/kg to which UFT gave little toxicity, the survival period was shown to be superior to the case of maximum tolerated dose (25.0 mg/kg per day). Next, we compared the maximum increase of life span (ILS) value for an administration schedule of continuous 9 days and 5 weeks which mimics the clinical schedule and found that the ILS value in the latter group was superior to the former and UFT improved cachexia, in the same manner. In the following experiments, we have clarified that UFT decreased the level of both plasma interleukin-6 (IL-6) and tumorous prostaglandin E2 (PGE2) and it highly accelerated IL-6 production from Colon-26. These findings suggest that UFT therapy, in low-toxic dose, could be useful to cachectic patients with poor performance status.

Enhancing 5-fluorouracil cytotoxicity by inhibiting dihydropyrimidine dehydrogenase activity with uracil in human tumor cells.

We analyzed dihydropyrimidine dehydrogenase (DPD) activity (radioenzymatic assay) and 5-fluorouracil (5-FU) cytotoxicity (MTT test) in the absence or presence of uracil in two human cancer cell lines, MIAPaCa-2 (pancreas tumor) and HuTu80 (duodenum tumor). Basal DPD activities in both were comparatively high; MIAPaCa-2, 101 and HuTu80, 153 pmol/min/mg protein, respectively. Twenty mu g/ml of uracil, a dose which did not influence cell proliferation, enhanced 5-FU cytotoxicity; MIAPaCa-2, 2.0-fold and HuTu80, 1.5-fold, respectively. Uracil inhibited both DPD activity and cell growth in a concentration-dependent manner, and exhibited maximum effect at molar ratios to 5-FU of more than 10 (DPD activity, almost complete inhibition; growth-inhibitory effect, about a 30% increase). In addition, the cytosolic DPD activity of OCC-1 human head and neck tumors, collected following the oral administration of ss mg/kg of uracil to tumor-bearing nude mice, decreased to about 50% of that of OCC-1 tumors not treated with uracil. These findings suggested that combined fluoropyrimidine and uracil treatment of tumors with high basal DPD, elicits a greater antitumor effect than fluoropyrimidines alone, since uracil could inhibit the degradation of 5-FU in the tumor. UFT, an oral fluoropyrimidine combined with uracil, is expected to be more effective in such tumors.

Preclinical antitumor efficacy of S-1: a new oral formulation of 5-fluorouracil on human tumor xenografts.

S-1 is a new oral formulation of 5-fluorouracil (5-FU) consisted of 1M tegafur, 0.4M 5-chloro-2,4-dihydroxypyridine that inhibits a degradation of 5-FU, and 1M potassium oxonate that regulates the phosphorylation of 5-FU in the gastrointestinal tract, and has shown excellent antitumor efficacy against various murine tumors in rodents, compared to the oral tegafur-based antitumor drug, UFT (1M tegafur plus 4M uracil), which is used clinically in Japan. To assess the possibility of clinically using S-1, we investigated the antitumor effect of S-1 on various human solid tumor xenografts in athymic rats and mice. In the nude rat system, S-1 was significantly effective against all 12 tumor xenografts tested when its minimum toxic dose (15 mg/kg) was administered for 14 days. Three tumors, stomach (H-81), colon (KM12C) and breast (H-31) markedly regressed in response to treatment with S-1 but not with UFT. The antitumor potency of S-1 was weak against human tumors xenografted into nude mice and likely similar to that of UFT. The reason of the discrepancy in the efficacy of S-1 between rats and mice was found to be that the 5-FU levels in the blood and tumor tissue of rats after oral administration of S-1 persisted much longer than in mice, and this prolonged maintenance of plasma 5-FU levels was significantly related to the potent antitumor activity of S-1. In conclusion, the results of this study suggested that based on its biological and pharmacokinetic characteristics, oral S-1 should be active against various human cancers.

Estrogen agonistic/antagonistic effects of miproxifene phosphate (TAT-59)

PURPOSE: We evaluated miproxifene phosphate (TAT-59) to elucidate its efficacy in antiestrogen therapy for breast cancer patients and to assess its tissue-selective estrogenic/antiestrogenic activity. METHODS: Using DP-TAT-59, a major and active metabolite of TAT-59, an in vitro cell growth inhibition test was performed. Antitumor activity was determined using TAT-59 against human tumor xenografts of the MCF-7 and the Br-10 cell lines and MCF-7-derived tamoxifen-resistant cell lines, R-27 and FST-1. The antitumor activity of DP-TAT-59 and DM-DP-TAT-59, major metabolites of TAT-59 found in human blood following a TAT-59 dose, was also examined after intravenous administration to experimental animals. The residual estrogenic activity of TAT-59, evaluated in terms of bone and lipid metabolism in ovariectomized rats, was then compared with that of tamoxifen. RESULTS: DP-TAT-59 significantly inhibited the proliferation of estrogen receptor-positive MCF-7 and T-47D tumor cells in the presence of 1 nM estradiol. TAT-59, given to mice bearing MCF-7 or Br-10 xenografts, at the dose level of 5 mg/kg, exerted a significant growth inhibitory effect that was stronger than that of tamoxifen. Moreover, R-27 and FST-1 tumors, which show a resistance to tamoxifen, responded strongly to TAT-59, suggesting that TAT-59 might be effective against tumors resistant to tamoxifen. The metabolites of TAT-59, DP-TAT-59 and DM-DP-TAT-59, showed similar antitumor activity. Both TAT-59 and tamoxifen suppressed the decrease in bone density and reduced the blood cholesterol levels in ovariectomized rats, suggesting that the estrogenic activity of TAT-59 is comparable to that of tamoxifen. CONCLUSIONS: On the basis of the above results, one may expect TAT-59 to become an effective drug in patients with tumors less sensitive to tamoxifen, while its estrogenic activity as determined by bone and lipid metabolism is similar to that of tamoxifen.

MR of the base of the pons in Wilson disease.

The authors describe unusual MR findings in three patients with Wilson disease, eg, white matter changes in the base of the pons, and speculate whether the changes are caused by Wilson disease or by concomitant disease, and whether the pontine lesions they observed are primary or related to lesions located more rostrally.

Experimental postoperative adjuvant chemotherapy by UFT using primary tumor amputation model.

We evaluated the postoperative adjuvant chemotherapy by UFT using the primary tumor amputation-pulmonary metastasis model. When Lewis lung carcinoma (LLC) primary tumors on the hind foot pad grew palpable, they were amputated on two different days. In experiment (A) (earlier amputation model), micrometastases were detected on the day of amputation only by the histopathological examination. In the experiment (B) (later amputation model), nodules could be determined even by necropsy. Long-term (60-day) consecutive administration of UFT (22 mg/kg/day), which produced no body weight loss, markedly prolonged the survival period in experiment (A) (ILS: over 118%), 1 of the 15 mice being cured. UFT had a relatively weak but significant effect (67% of ILS) in schedule (B). Using the same model, we examined the inhibitory effect of UFT (2-week administration) on the number of metastatic nodules. A significant decrease of metastatic nodules was observed by UFT with both amputation schedules, but its effect was superior with schedule (A). In the same model using Colon 26 PMF-15, UFT markedly prolonged the survival period of mice (150% of ILS) and significantly decreased the metastatic nodules (86% inhibition). The dose of UFT used was relatively low, and did not significantly inhibit the growth of large tumors. However, the sensitivity to the micrometastases was high. These findings suggest that the postoperative adjuvant chemotherapy by the long-term consecutive administration of UFT would be effective for clinical cancer especially in curatively resected cases.

Activity of menogaril against various malignant lymphoma cell lines and a human lymphoma xenograft in mice.

Menogaril is an antitumor agent different from other anthracyclines in that it is active after oral administration; therefore, extravasation is not a side effect. In this basic study, we examined the antitumor activity of menogaril against malignant lymphoma. We compared its activity towards experimental malignant lymphoma with that of Adriamycin, epirubicin, pirarubicin, vincristine, and etoposide, treating mice with each drug at the dose schedule usually used for patients. Menogaril rapidly penetrated lymphoma cells and remained there at least 3 hours after the drug was washed out. Menogaril cleaved more double-stranded DNA in lymphoma cells than Adriamycin, epirubicin, pirarubicin, or etoposide. Menogaril had stronger antitumor activity against experimental malignant lymphoma in mice than Adriamycin, epirubicin, vincristine, and etoposide. Menogaril significantly lengthened the life span of mice bearing one of three lymphoma cell lines resistant to cisplatin, vincristine, or cyclophosphamide. Menogaril had stronger antitumor activity against the human malignant lymphoma xenograft LM-3 than Adriamycin. The strength of the cytotoxic activity of Menogaril might arise from its ready penetration into cells and its cleavage of double-stranded DNA. Therefore, Menogaril might become a useful drug for the treatment of patients with malignant lymphoma by oral administration; 7 days of administration was effective in the in vivo experiments.