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S Tsukagoshi

Publications and source records attributed to S Tsukagoshi.

At least 145 records · Page 8Linked to original sources
PubMed1985

[Experimental studies with the use of metastatic clones isolated from mouse tumors].

Low and high metastatic clones were isolated from mouse colon 26 by repeated cloning of tumor cells in the lung. These clone cells showed an interesting metastatic capacities, low and high lung metastasis. The results indicate that original tumor consisted of various and heterogeneous cell clones having different metastatic capacities. Using highly metastatic clones, NL-17 and B16-F10 and B16-BL6, adriamycin and 5-fluorouracil were found similarly effective to both parental and cloned tumor lines. Although there are several reports to indicate heterogeneous drug sensitivity of metastatic clones from the parental line, present study indicated the similar drug sensitivity. Therefore, heterogeneity of drug sensitivity is scheduled to check with different antitumor drugs.

Adenocarcinoma↗
PubMed1985

Cure of mice bearing P388 leukemia by vincristine in combination with a calcium channel blocker.

Mice inoculated with P388 leukemia were treated initially with vincristine (VCR) at a dose of either 1.5 or 2.0 mg/kg. After 1 week, VCR alone (0.1 mg/kg) was given daily for ten treatments, but no mice were cured with this regimen. However, when the calcium channel blocker verapamil (75 mg/kg) was administered with VCR at 1.5 or 2.0 mg/kg, lifespans were prolonged and one of ten or six of ten mice were cured, respectively. As reported previously, verapamil renders less sensitive or resistant tumor cells susceptible to VCR by inhibiting the VCR efflux mechanism, especially in resistant cells. Therefore, verapamil in combination with VCR apparently can result in total cell kill under the conditions used.

Animals↗
PubMed1985

[Antitumor activities of orally administered 4-carbamoylimidazolium-5-olate (SM-108)].

We investigated the antitumor effect of orally administered SM-108. The drug showed strong antitumor activities against Ehrlich carcinoma, sarcoma 180, P388 leukemia, L1210 leukemia, colon 26 adenocarcinoma, colon 38 adenocarcinoma, and Lewis lung carcinoma. The antitumor activity of SM-108 against Ehrlich carcinoma was so remarkable, in fact, that all mice in a group survived for a long time. The antitumor effect of SM-108 depends on its administration schedule. Treatment involving a schedule of one dose every 6 h for 24 h at intervals of 3 days brought about a much stronger effect than daily single treatment. The maintenance of a high serum level of SM-108 for 24 h by the former treatment is responsible for the strong therapeutic effects, because the action of SM-108 is time-dependent. The antitumor activities of SM-108 administered orally are excellent enough to be comparable with those obtained by intraperitoneal administration as previously reported.

Administration, Oral↗
PubMed1984

Krestin (PSK).

A polysaccharide preparation isolated from Coriolus versicolor (Fr.) Quél. of Basidiomycetes (PSK) predominantly consists of glucan and approximately 25% tightly bound protein. PSK was effective against various allogeneic and syngeneic animal tumors and has been given orally to cancer patients. Various suppressed or enhanced immune responses of tumor-bearing animals were restored to normal levels by the administration of PSK in the tumor models tested. The killer T cell activity was augmented in tumor-bearing mice by intraperitoneal or oral administration of PSK, and there was correlation between the PSK associated antitumor effect and the killer T cell activity. It was found that PSK competed with immunosuppressive substances isolated from tumor-bearing mice and that the intestinal immune system appeared to be modulated by oral administration of PSK. After oral administration of 14C- or 35S-labeled PSK to normal rats, it was found that small or large molecular substances appeared in the serum depending on the time elapsed after administration, an indication that large molecular size products were from the digestive tract.

Amino Acids↗
PubMed1984

Quantitative approach to determine the application time of the left ventricular assist device.

This study was designed to establish a method for determining the optimal time of the application of the left ventricular assist device from the viewpoint of the metabolism of the vital organs. Quantitative systemic low flow states were made utilizing goats with total artificial hearts. During these experiments, arterial lactate and pyruvate values were sequentially measured. The behavior of anaerobic metabolism during low cardiac output states and in the recovery process following normalization of the cardiac output was quantitatively described and evaluated. The experimental results are summarized as follows: If a time when the decay of arterial lactate ceases at a level above the normal level by greater than 30 mg/dl is observed despite the use of intraaortic balloon pumping, that time is the exact optimal time for application of the left ventricular assist device. There is a great possibility that circulatory failure will be irreversible if left ventricular assist pumping is not initiated before the arterial lactate value increases to greater than or equal to 140 mg/dl. The method of evaluating the alteration of anaerobic metabolism described in this study is useful for determining the application time of the left ventricular assist device.

Animals↗
PubMed1984

Effects of quinidine and related compounds on cytotoxicity and cellular accumulation of vincristine and adriamycin in drug-resistant tumor cells.

Quinidine, which has antiarrhythmic activity, greatly enhanced the cytotoxicity of vincristine (VCR) in tumor cells and especially in VCR-resistant sublines of P388 leukemia (P388/VCR) and human myelogenous leukemia. A nontoxic concentration of quinidine increased VCR cytotoxicity in these resistant tumor cells about 50 to 80 times, and the drug in combination with VCR could completely reverse VCR resistance of these cell lines. Quinidine also enhanced the cytotoxicity of Adriamycin, especially in the Adriamycin-resistant subline of P388 leukemia; this enhancement (8-fold) was less than that of VCR toxicity in the VCR-resistant tumor line. When administered daily for 10 days with VCR, quinidine at doses of 50 to 125 mg/kg significantly enhanced the chemotherapeutic effect of VCR in P388/VCR-bearing mice. Some other antiarrhythmic agents also showed similar effects in vitro, but these effects were considerably lower than that of quinidine. Quinidine increased the cellular levels of VCR and daunomycin in VCR-resistant sublines of mouse and human tumors and the ADM-resistant mouse tumor line in vitro, respectively. Quinidine also enhanced the cellular accumulation of VCR in P388/VCR cells in vivo. Thus, the therapeutic effect observed in P388/VCR-bearing mice might be due to the enhanced accumulation of VCR in P388/VCR cells by quinidine. The increase of cellular accumulation of VCR was partly explained by inhibition of efflux of VCR and daunomycin from the resistant tumor cells. The mechanism of this phenomenon is discussed in relation to previous findings on calcium channel blockers.

Animals↗
PubMed1984

Spontaneous metastasis of highly metastatic variants of mouse tumors and the effect of drugs on the metastasis.

Spontaneous metastasis of highly metastatic variants, B16 melanoma BL-6 and colon adenocarcinoma 26 NL-22, was examined. Tumor cells were inoculated into the right front footpad and the original tumors were removed by amputation of the forelimb at an appropriate time after tumor inoculation. Spontaneous lymph node and lung metastases occurred with B16 BL-6 and spontaneous lung metastasis occurred with NL-22. Analysis of the time-dependent formation of lymph node and lung metastases of BL-6 indicated that lung metastasis could be formed after the lymph node metastasis. Metastasis is influenced by the mouse strain, and both inbred and F1 hybrid mice of syngeneic origin could be used as host animals. By using these metastatic variants, two spontaneous metastasis systems were established. In order to evaluate the systems, the effects of 5-fluorouracil (5-FU) and adriamycin (ADM) were examined. 5-FU was effective against the metastases of both tumors, and ADM was moderately effective against B16 BL-6 metastasis.

Adenocarcinoma↗
PubMed1984

Establishment of human KB cells resistant to 1-beta-D-arabinofuranosylcytosine, and mechanisms of cellular resistance in isolated clones.

A subline of human KB cells that was resistant to 1-beta-D-arabinofuranosylcytosine (ara-C) was established by continuous exposure of the cells to increasing concentrations of ara-C. Thirteen resistant clones were isolated from the resistant subline (KB/ara-C). KB/ara-C showed 1,300-fold higher resistance than the parent KB cells to ara-C; the most resistant clones, clones 7 and 10, showed 1,330-fold higher resistance. In the absence of ara-C, the resistance of the parent KB/ara-C cells was stable for at least 14 weeks, whereas that of clone 7 was stable for 10 weeks, but was slightly less after 14 weeks. The ara-C kinase and ara-C deaminase activities of the 13 clones and the cellular uptake of ara-C by several clones were measured. In general the clones showed decreased deoxycytidine kinase activity and decreased cellular uptake of ara-C. Most clones had higher cytidine deaminase activity than KB cells, but some had activity similar to that of the KB cells. A clear inverse relationship was found between the ara-C sensitivity of the clones and their kinase activity, but not their deaminase activity or their ara-C uptake. These results clearly demonstrate that a major mechanism of ara-C resistance of these human KB cells was a decrease in the activity of the ara-C activating enzyme deoxycytidine kinase. The parent KB/ara-C cells showed no clear cross-resistance to various antitumor agents other than an ara-C derivative, including metabolic inhibitors, alkylating agents, DNA binders and mitotic spindle poisons.

Antineoplastic Agents↗
PubMed1984

High calcium content of pleiotropic drug-resistant P388 and K562 leukemia and Chinese hamster ovary cells.

The calcium content of pleiotropic drug-resistant tumor cells was estimated and compared with that of the parent tumor lines. P388 leukemia cells resistant to vincristine and Adriamycin contained more calcium (1.5- to 1.8-fold) in the cells and on the cell surface than the parent P388 cells. Similar results were obtained with human K562 myelogenous leukemia cells resistant to vincristine and also with Chinese hamster ovary cells resistant to colchicine. However, the calcium content of P388 cells resistant to 5-fluorouracil was almost the same as that of the parent P388 cells. The calmodulin content of pleiotropic resistant tumor lines and a 5-fluorouracil-resistant tumor line was almost the same as that of the corresponding parent lines. The isolated plasma membrane of K562 cells resistant to vincristine contained approximately 1.5-fold higher calcium than the parent cells. These results indicate that the higher cellular calcium content might be a characteristic phenotype of pleiotropic resistant tumor lines.

Animals↗
PubMed1984

Antitumor effects and pharmacology of orally administered N4-palmitoyl-1-beta-D-arabinofuranosylcytosine in mice.

The antitumor activity and the pharmacological fate of N4-palmitoyl-1-beta-D-arabinofuranosylcytosine (N4-palmitoyl-ara-C) administered p.o. were examined in mice and were compared with those of the parent compound 1-beta-D-arabinofuranosylcytosine (ara-C). N4-Palmitoyl-ara-C administered p.o. showed chemotherapeutic effects superior to those of ara-C when used against P388 leukemia, L1210 leukemia, mammary adenocarcinoma 755, and colon 38 adenocarcinoma. The derivative also inhibited the spontaneous pulmonary metastasis of s.c.-inoculated Lewis lung carcinoma more efficiently than did ara-C. After a single p.o. injection of a suspension of N4-palmitoyl-[2-14C]ara-C at a therapeutic dose of 350 mu/kg, a high concentration of the drug was found in the liver, lung, and plasma of portal venous blood. The level of the drug in other tissues and peripheral plasma was rather low. The two main metabolites, identified as ara-C and 1-beta-D-arabinofuranosyluracil, were found in plasma and various tissues. Plasma ara-C concentration was maintained for at least 6 hr in the range of 2.3 to 5.1 nmol/ml after p.o. administration of N4-palmitoyl-ara-C (350 mu/kg). On the other hand, when an equimolar amount of ara-C was given, the plasma levels of the drug decreased rapidly; from 2 to 6 hr after administration, the level (1.0 to 4.1 nmol/ml) was less than that obtained with N4-palmitoyl-ara-C. These results suggested that N4-palmitoyl-ara-C administered p.o. is absorbed as an intact form from the gastrointestinal tract and that the absorbed compound is the depot form of ara-C, releasing ara-C over a prolonged period of time.

Adenocarcinoma↗
PubMed1984

Purification and characterization of an amidohydrolase for N4-long-chain fatty acyl derivatives of 1-beta-D-arabinofuranosylcytosine from mouse liver microsomes.

N4-Long-chain fatty acyl-1-beta-D-arabinofuranosylcytosine amidohydrolase, a metabolizing enzyme for N4-acyl derivatives of 1-beta-D-arabinofuranosylcytosine with long-chain fatty acids, was purified from mouse liver microsomes. The purification was accomplished by solubilization of liver microsomes with Triton X-100, diethylaminoethyl cellulose chromatography, gel filtrations, hydroxyapatite chromatography, and concanavalin A:Sepharose chromatography. On sodium dodecyl sulfate:polyacrylamide gel electrophoresis, the purified enzyme preparation produced a single protein band with a molecular weight of 54,000. The enzyme had an optimal pH of 9.0, and the Michaelis constant for N4-palmitoyl-1-beta-D-arabinofuranosylcytosine was 67 microM. The thiols such as dithiothreitol or 2-mercaptoethanol stabilized the enzyme and stimulated its activity. p-Chloromercuribenzoate, N-ethylmaleimide, diisopropylfluorophosphate, and phenylmethylsulfonyl fluoride strongly inhibited the reaction. Bovine serum albumin markedly stimulated the enzyme activity, whereas detergents such as Triton X-100, deoxycholate, and sodium dodecyl sulfate had little effect. The enzyme did not require monovalent or divalent cations. Among the series of N4-acyl derivatives of 1-beta-D-arabinofuranosylcytosine with different chain lengths of acyl residues, the purified enzyme preferentially hydrolyzed the derivatives with long-chain fatty acids (C12 to C18), and N4-palmitoyl-1-beta-D-arabinofuranosylcytosine was the most susceptible. The purified enzyme was inactive on various N-acylamino acids, amides, oligopeptides, proteins, N-acylsphingosines (ceramides), triglyceride, lecithin, and lysolecithin. These results suggest that N4-long-chain fatty acyl-1-beta-D-arabinofuranosylcytosine amidohydrolase may be a new type of linear amidase.

Amidohydrolases↗
PubMed1984

Metastasis after intravenous inoculation of highly metastatic variants of mouse tumors and the effects of several antitumor drugs on the tumors.

Tumor metastasis was examined after iv inoculation of highly metastatic variants of mouse tumors. Highly metastatic variants, B16-F10 and B16-BL6, of B16 melanoma origin and colon 26 NL-17 of colon adenocarcinoma 26 origin were used in the experiments. Formation of pulmonary metastasis was influenced by the mouse strain and age. Based on the results, experimental metastasis systems of these tumors were established, and the effects of chemotherapeutic agents were examined. 5-Fluorouracil and adriamycin were significantly effective for the suppression of pulmonary metastasis. The degrees of suppression of metastasis by these drugs were different with different tumor variants, but the sensitivity of the metastasis to the drug was similar to that of the parent tumor. Several aspects of the chemotherapy of metastasis are discussed.

Adenocarcinoma↗
PubMed1984

Isolation and characterization of highly and rarely metastatic clones from murine colon adenocarcinoma 26.

Three typical metastatic clones, designated N-1, N-4, and N-5, were isolated in vitro from a murine colon adenocarcinoma 26 cell line (Colon 26). The incidence of spontaneous metastasis was highest in N-4 (85%), moderate in N-5 and Colon 26 (50 and 53%, respectively) and lowest in N-1 (0%). The major target organ of metastasis was the lung. Among the clones, N-4 showed higher lung colonizing potential after intravenous inoculation, higher tumorigenicity and higher saturation density in culture. Cell-surface analysis of cloned cells by 125I-labeled lectins revealed significant reduction of the number of concanavalin A (Con A)-binding sites in highly metastatic N-4 cells. In sodium dodecyl sulfate-slab gel analysis of cellular glycoproteins, a 94,000-dalton component, which is reactive to Con A, was more intensely observed in N-1 as compared with other clones and parental Colon 26. These clones could provide a new model for the study of metastasis of colon carcinoma.

Adenocarcinoma↗
PubMed1983

Potentiation of chemotherapeutic effect of vincristine in vincristine resistant tumor bearing mice by calmodulin inhibitor clomipramine.

Clomipramine, which is used as antidepressant and possesses calmodulin inhibitory activity, circumvented partly the vincristine resistance in vivo. Although vincristine alone at 30-200 micrograms/kg did not confer a significant therapeutic effect in vincristine resistant P388 leukemia (P388/VCR)-bearing mice, clomipramine at doses of 20 to 50 mg/kg administered daily for 10 d with vincristine enhanced the chemotherapeutic effect of vincristine in P388/VCR-bearing mice. Approximately a 30% increase in life span occurred. Although the circumvention of vincristine resistance was not achieved perfectly, it could be speculated that more than 98-99% of vincristine resistant tumor cells which could not be killed by vincristine alone could be killed by this approach.

Animals↗
PubMed1983

[Studies and progress on the enhancement of therapeutic effects of antitumor drugs].

Progress of cancer chemotherapy has been mainly owed to the development of new antitumor drugs and the devices for enhancing the therapeutic effect of antitumor drugs. As for the enhancement of therapeutic effect, there are three major devices, that is, 1) a device to enhance the therapeutic effect by changing drug formulation, 2) enhancement of therapeutic effect by the combination of antitumor drugs with other treatment modalities and 3) enhancement by the combination with non-antitumor drugs. In this paper, major topics of these recent studies in Japan were reviewed. Especially, experimental studies on the enhancement of antitumor effect by the combination of antitumor drugs with calcium or calmodulin inhibitors and also overcome of vincristine resistance by the combination of vincristine with a calcium antagonist, verapamil, were described.

Amphotericin B↗
PubMed1983

Establishment and properties of vincristine-resistant human myelogenous leukemia K562.

A vincristine (VCR)-resistant subline of human K562 myelogenous leukemia was established in vitro, and several clones with different susceptibilities to VCR were isolated by the limiting dilution technique. The most resistant clone (H-1) had a 17-fold greater resistance to VCR when compared to the parent K562 cells. The clone gradually lost the resistance during prolonged culture in vitro. These clones generally accumulated smaller amounts of VCR in their cells as compared to the parent cells. The size of H-1 clone cells was almost the same as that of the parent cells. The numbers of potential binding sites of VCR in the K562 cells and the resistant H-1 clone were almost the same. Similar results were obtained for P388 and its VCR-resistant subline. The cells derived from the VCR-resistant H-1 clone were highly cross-resistant to vindesine and moderately resistant to vinblastine. Cells derived from clone H-1 exhibited marginal degrees of cross-resistance to adriamycin, maytansine and VP-16-213, whereas VCR-resistant P388 leukemia cells exhibited significant resistance to these agents, especially to maytansine.

Cell Line↗