Biomedical subjects
Publications and source records attributed to H Kudo.
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The object of this study was to evaluate activities of thymidylate synthetase (TS) and thymidine kinase (TK) in relation to histopathological features of human mammary carcinomas, as well as clinical classification of patients. The TS and TK are key enzymes on the de novo and salvage pathways, respectively, for pyrimidine nucleotide synthesis. High TS and TK activities have been found in rapidly proliferating tissues. Clinical stage and TNM post-surgical histopathological classification of 20 patients with mammary carcinomas, during the period of 1988-1991, and TS and TK activities in each carcinoma were determined. Elevated TS and TK activities in mammary carcinomas corresponded to progressively worse clinical stages. Papillotubular carcinomas showed lower enzyme activity than that of solid-tubular and scirrhous types. TS activities continued to rise as the malignant invasion became more severe. The clinical prognosis of patients with mammary carcinomas appears to depend on the de novo synthesis of DNA in carcinomas.
We investigated the synergistic efficacy of CDDP and UFT, an oral anticancer derivative of 5-fluorouracil, on DNA synthesis of 3'-MeDAB-induced hepatocarcinomas in rats. Chronic treatment with CDDP slightly reduced tissue activities of thymidylate synthetase and thymidine kinase in the hepatocarcinomas, and, moreover, simultaneous administration of a low dose of UFT with CDDP markedly suppressed both enzyme activities, i.e., UFT and CDDP showed a potent synergism on DNA synthesis in hepatocarcinomas.
The suppressive effects of danazol, an isoxazol derivative of a synthetic steroid 17 alpha-ethinyltestosterone, on cellular viability and DNA synthesis in 7,12-dimethylbenz(a)anthracene induced mammary tumours were investigated in adult female rats by enzyme assays and immunohistochemistry with bromodeoxyuridine (BrdU). Rats treated with danazol for 30 days showed a decrease of plasma levels of luteinizing hormone and estradiol associated with a dysfunction in hypothalamo-hypophysial-gonadal axis, resulting in lower activities in succinate dehydrogenase and thymidine kinase, and a reduction of BrdU-immunoreactive cells in mammary tumours compared with the control, i.e., decreases of viability and pyrimidine nucleotide synthesis in tumour cells in danazol-treated rats.
A synthetic analog of ethinyltestosterone, Danazol, has been used clinically for the treatment of immune thrombocytopenia. We investigated the effects of Danazol on thrombopoiesis in normal rats. Though 4-week treatment by Danazol slightly enhanced the DNA synthesizing enzyme activities and the number of S-phase cells in bone marrow and spleen, the number of megakaryocytes and thrombocytes were not increased in bone marrow and peripheral blood, respectively. These findings suggest that Danazol treatment will not induce thrombosis with thrombocytosis in normal human beings and animals.
In an attempt to define a regulation of pyrimidine nucleotide synthesis in hematopoietic cells, we investigated the activities of thymidylate synthetase and thymidine kinase, and the cell cycle by flow cytometric DNA analysis and bromodeoxyuridine-immunohistochemistry during the recovery phase of hematopoietic cells in bone marrow after the hypoplastic period induced by cyclophosphamide treatment in rats. The hematopoietic cells first entered into cell cycle via the de novo pathway in pyrimidine nucleotide synthesis, and were secondly proliferated and differentiated via the salvage pathway. S-phase cells associated with a myeloid hematopoiesis increased earlier than those associated with an erythroid hematopoiesis in the recovery phase of in rat bone marrow.
We examined the effects of an application of 5-fluorouracil (5-FU) ointment and a chronic oral administration of 1-(2-tetrahydrofuryl)-5-FU plus uracil (UFT) on 7,12-dimethyl-benz(a)-anthracene-induced squamous cell papillomas in mice. Although application of 5-FU ointment reduced the growth of papillomas slightly, chronic oral administration of UFT could prevent tumorigenesis and suppress the growth of papillomas, resulting in the reduction of the tumorous viability and DNA synthesis.
Buserelin, a potent LH-RH agonist, has been used for the treatment of hormonal disorders such as precocious puberty, endometriosis, cystic mastitis and prostatic carcinoma. Prolonged treatment with buserelin has been known to induce a refractory phase of pituitary desensitization. In the present study, we found that two-week treatment with buserelin strongly suppressed the activities of thymidylate synthetase and thymidine kinase, and markedly reduced the appearance of BrdU-immunoreactive (S-phase) cells in both prostate glands and uteri in male and female adult rats, respectively.
In an attempt to define the efficacy of hormone replacement therapy in postmenopausal osteoporosis, we investigated the effects of estrone with or without medroxyprogesterone acetate on the bone mineral density of the femur of aged rats, of which plasma levels of luteinizing hormone (LH), follicle stimulating hormone (FSH) and estradiol were markedly reduced in comparison with those of younger rats. Although additional sex hormones had little effect on the plasma levels of gonadotropins, chronic administration of estrone significantly enhanced the bone mineral density of femur in aged animals.
Propolis is a resinous material gathered by honey bees from the buds and bark of certain trees and plants, and used inside their hives. Characteristic components of propolis are many kinds of flavonoid aglycones. The methanol extract of a Brazilian propolis was fractionated by HPLC, and a tumoricidal substance was isolated and characterized as a new clerodane diterpenoid (PMS-1) with a molecular formula of C20H32O3 (MW: 320). We investigated the effects of PMS-1 on skin tumorigenesis and the development of skin tumors induced by 7,12-dimethylbenz(a)anthracene application on mouse back skin. It was tentatively concluded that PMS-1 reduced the incidence of skin tumors by inhibition of DNA synthesis in a de novo pathway, and suppressed the growth of the tumors by decreasing DNA synthesis in a salvage pathway.
The effects of macrophage (M) and granulocyte (G) colony-stimulating factors (CSFs) on the activity of thymidylate synthase and thymidine kinase, which are involved in de novo and salvage pathways for pyrimidine nucleotide synthesis, were investigated in the hematopoietic cells of rats treated with cyclophasphamide. Thymidine kinase activity, but not that of thymidylate synthase, was markedly enhanced in these cells by M- and G-CSF treatment (p < 0.05 and p < 0.01). G-CSF directly, and M-CSF indirectly stimulate myeloid cells and lead to S-phase predominantly via the salvage pathway for pyrimidine nucleotide synthesis. The present study indicates that these CSFs can be effective inducers of complete remission in acute leukemias when employed together with chemotherapy.
Although hormone replacement therapy not only relieves vasomotor symptoms but also reduces cardiovascular disease and osteoporosis, long-term estrogen therapy increases the risk of endometrial and/or mammary cancer. We investigated the effects of conjugated estrogens with or without medroxyprogesterone acetate in oophorectomized, 7,12-dimethylbenz(a)anthracene-treated rats. Chemically induced mammary carcinogenesis was completely suppressed by the simultaneous oophorectomy, but conjugated estrogens replacement with or without medroxyprogesterone acetate markedly stimulated mammary carcinogenesis in the ovariectomized rats. The chronic administration of conjugated estrogens and medroxyprogesterone acetate markedly reduced the activities of thymidylate synthetase and thymidine kinase and bromodeoxyuridine-immunoreactive (S-phase) cells in mammary tumors. These results indicate that the treatment using conjugated estrogens with or without medroxyprogesterone acetate may promote the mammary carcinogenesis in postmenopausal women but the chronic administration of medroxyprogesterone acetate may alter the development of established mammary cancer.
We investigated the effects of tamoxifen on the growth of 7,12-dimethylbenz(a)anthracene induced rat mammary tumors, the activity of thymidylate synthetase and thymidine kinase (key enzymes involved in de novo and salvage pathways for pyrimidine nucleotide synthesis), and also their gene expression. The effects on immunohistochemistry using bromodeoxyuridine in the tumors and bone mineral density of the femur in rats were also studied. Chronic administration of tamoxifen markedly reduced the expression of thymidylate synthetase mRNA, followed by a reduction in enzyme activity and S-phase cells in the mammary tumors, and significantly enhanced the bone mineral density. Tamoxifen not only attenuated bone loss in aging but also enhanced bone volume in mammary tumor-bearing rats in which tumor growth was suppressed via both the de novo and salvage pathways for pyrimidine nucleotide synthesis.