Satoe Suzuki

Anticancer effects of a chinese Herbal medicine, Juzen-taiho-to, in combination with or without 5-fluorouracil derivative on DNA-synthesizing enzymes in 1,2-dimethylhydrazine induced colonic cancer in rats

Juzen-taiho-to (JTT; [Shi-quan-da-bu-tang], a Japanese modified Chinese herbal prescription) in combination with an anticancer drug UFT (5-fluorouracil derivative) prevented the body weight loss and the induction of the colonic cancer in rats treated with a chemical carcinogen 1,2-dimethylhydrazine (DMH), and suppressed markedly the activity of thymidylate synthetase (TS) involved in the de novo pathway of pyrimidine synthesis in colonic cancer induced by DMH.

Splenomegaly induced by recombinant human granulocyte-colony stimulating factor in rats

Spontaneous ruptures of the spleen have been observed in donors and patients with malignancy during mobilization of peripheral blood stem cells. Thus, we investigated the morphological and histological alteration of the spleen, and mRNA expression levels and activities of the DNA-synthesizing enzymes thymidylate synthase (TS) and thymidine kinase (TK) in the splenic cells, of rats treated with recombinant human granulocyte-colony stimulating factor (rhG-CSF). Daily injections of rhG-CSF for 5 or 7 days slightly enhanced the splenic weight. Single or 3-day treatment with rhG-CSF markedly enhanced the number of granulocytes in peripheral blood. Expression levels of TS and TK mRNA in the splenic cells were significantly increased 6 hours after rhG-CSF treatment. Early expression of TS and TK mRNA in the splenic cells may indicate a reseeding of hematopoietic cells from the bone marrow. Daily injections with rhG-CSF enhanced the TS and TK activities in the splenic cells. As continuous elevations of DNA-synthesizing enzyme activity and spleno-megaly are suggestive of a possible splenic rupture, the monitoring of peripheral granulocytes and splenic size is necessary during the rhG-CSF treatment.

Increase of DNA Synthesis in Uterine Adenomyosis in Mice with Ectopic Pituitary Isograft

Ectopic pituitary isografts (EPI) have been found to induce a high incidence of uterine adenomyosis in SHN mice. All the SHN mice given EPI in the right uterus at 40 days of age developed uterine adenomyosis, and more than 80% of mice showed the genesis of subserosal nodules, an advanced state of adenomyosis, 65 days after EPI. Activities of both thymidylate synthetase and thymidine kinase, i.e. DNA-synthesizing enzymes in de novo and salvage pathways of pyrimidine metabolism, respectively, were significantly increased in EPI-induced uterine adenomyosis to approximately 2-fold those in normal control uteri. Bromodeoxyuridine-immunoreactive cells were regarded as the cells in S phase, and the number in the endometrial epithelium and stroma in EPI-induced uterine adenomyosis was more than 1.5-fold that in normal control uteri. EPI may affect the genesis of uterine adenomyosis generally, but not locally, because there were no differences between the right uterus with EPI and the left without EPI in the incidence of adenomyosis, histology or DNA-synthesizing enzyme activities.

Chemopreventive effect of a vitamin D3 analog, alfacalcidol, on colorectal carcinogenesis in mice with ulcerative colitis

An increased incidence of colorectal carcinoma is known to occur in patients with ulcerative colitis (UC), which displays a cycle of recurrence–remission in the colorectal mucosa. Repeated oral doses of 3% dextran sulfate sodium subsequent to a single intraperitoneal injection of azoxymethane induced a chronic UC resulting in an increased incidence of high-grade dysplasia and submucosal-invasive adenocarcinomas in the mouse colorectum. The active form of vitamin D3 is a calcium-regulating hormone that increases serum calcium levels and intestinal calcium absorption. It has been reported that there is an inverse correlation between serum levels of the active metabolite of vitamin D and colorectal carcinoma stage. The features of the colitis induced in this animal model are very similar to the UC in patients in terms of both clinical and histological characteristics. Treatment with a vitamin D3 analog, alfacalcidol, in mice prevented colitis and carcinogenesis; this is shown by inhibition of the decrease in colorectal length and inhibition of the increased incidence of colorectal dysplasia, with a reduction in the mRNA expression of the DNA-synthesizing enzyme, thymidine kinase, in colorectal tissues.

Down regulation by a low-zinc diet in gene expression of rat prostatic thymidylate synthase and thymidine kinase

BackgroundZinc has a wide spectrum of biological activities and its deficiency is related to various abnormalities of cell metabolism.MethodsWistar male rats, at age of 4 weeks, were fed a low-zinc diet for six weeks. The levels of bromodeoxyuridine incorporated into the prostatic DNA and the mRNA expression levels of prostate thymidylate synthase and thymidine kinase were examined.ResultThe low-zinc diet caused a marked reduction in the body growth and organ weights, resulted in a low hematopoiesis, hypo-albuminemia and hypocholesterolemia. Although there were few differences in plasma biochemical markers, plasma levels of luteinizing hormone and testosterone were reduced by the low-zinc diet. Bromodeoxyuridine-immunoreactive (S-phase) cells and mRNA expression levels of thymidylate synthase and thymidine kinase in the prostate cells were markedly affected by the low-zinc diet.ConclusionA low-zinc diet appears to reduce the body growth and organ weights including prostate, causing low plasma levels of luteinizing hormone and testosterone and reduction in prostate DNA replication in growing-rats.

EARLY PROGRESSION FROM DIMETHYL SULFOXIDE-INDUCED G0/G1 ARREST IN L1210 CELLS

Recently, dimethyl sulfoxide (DMSO) has been used as a convenient cryoprotectant for stem cells in stem cell transplantation using allogenic peripheral blood or umbilical cord blood. As the stem cells have a multipotency, clarification of the extent of cell proliferation after transplantation is difficult. In the present study, DMSO gradually induced G0/G1 arrest in mouse leukemia L1210 cells with good cell viability. After removal of DMSO, the cells proliferated appropriately, resulting in expression of the DNA‐synthesizing enzymes thymidylate synthase and thymidine kinase within 6h, and the cells entering into S phase within 12h. The sequence was followed by the marked activation of both enzymes within 24h and the increase of bromodeoxyuridine (BrdU) immunoreactive (S phase) cells with rapid cell proliferation within 36h. In conclusion, mouse leukemia L1210 cells, which were treated with 1.5% DMSO for 96h, tolerated the treatment and reversed the cell cycle arrest within 36h.

Prevention of Osteopenia Induced with a Gonadotropin-Releasing Hormone Agonist in Rats

Abstract. We investigated the effects of conjugated estrogens as an add-back replacement drug, incadronate sodium as a bisphosphonate, and alfacalcidol as a vitamin D3 analog on femoral bone mineral density (BMD) and bone mineral content (BMC) in female rats chronically treated with the gonadotropin-releasing hormone (GnRH) agonist leuprorelin acetate. The chemical castration of the rats by the administration of GnRH agonist for 16 weeks reduced the BMD values to 92.3%, 91.3%, and 93.3% of those of the normal control animals in the whole femur, metaphysis, and diaphysis of the femur, respectively. The BMC value was decreased to 91.0% of that of the normal control animals by the chronic GnRH agonist treatment. However, a simultaneous 8-week administration of conjugated estrogens, bisphosphonate, and vitamin D3 analog markedly augmented the BMC values to 110.3%, 110.1%, and 114.4%, respectively, of those in the rats treated with the GnRH agonist alone. These findings indicate that antiosteoporotic agents could be useful for preventing induced osteopenia under the careful monitoring of biochemical markers of osteoblastic activity or bone resorption and BMD or BMC in patients undergoing GnRH treatment.

Pharmacotherapeutic Effects of Toki-shakuyaku-san on Leukorrhagia in Young Women

Toki-shakuyaku-san is a traditional Chinese herbal prescriptions that is composed of 6 herbal plants, i.e., peony root, atractylodes lancea rhizome, alisma rhizome, hoelen, cnidium rhizome and Japanese angelica root. Administration with Toki-shakuyaku-san normalized irregular menstrual cycle, healed cervical pseudo-erosion and reduced leukorrhagia in young women who had insufficient luteal function.

Additive effects of medroxyprogesterone acetate and 5-fluorouracil derivative on 7,12-dimethylbenz[a]anthracene-induced rat mammary tumors.

Chronic oral administration of 1-(2-tetrahydrofuryl)-5-fluorouracil in combination with uracil suppressed thymidylate syntetase (TS) gene expression followed by reduction of TS activity in rat mammary tumors induced with 7,12-dimethylbenz[a]anthracene. Addition of medroxyprogesterone acetate (MPA) to the anticancer drug caused an additional decrease in TS and thymidine kinase activities in the tumor growth and restoration of bone loss. These results suggest that the simultaneous adminstration of MPA and anticancer drugs causes increased inhibition of mammary tumor growth and also diminishes the bone loss.

Suppression by kampo medicine, sho-saiko-to, on papillomas induced by 7,12-dimethylbenz(a)anthracene in mice.

Sho-saiko-to (SST) is a Japanese modified, traditional Chinese herbal medicine (Kampo medicine) consisting of seven medical plants. We examined the effects of SST on formation and growth of squamous cell papillomas induced by 7,12-dimethylbenz(a)anthracene application in mouse skin. Chronic oral administration of SST reduced the incidence and growth of papillomas with the reduction of activities of succinate-dehydrogenase and thymidylate synthetase, which were evaluated as the cell viability and DNA synthesis via the de novo pathway, respectively.