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S Tsukagoshi

Publications and source records attributed to S Tsukagoshi.

At least 181 records · Page 10Linked to original sources
PubMed1981

Inhibition of lymph node metastasis of P388 leukemia by bestatin in mice.

Bestatin, a chemically defined immunostimulant of low molecular weight, suppressed the gradually-occurring lymph node metastasis of P388 leukemia in CDF1 mice when administered i.p. at the doses of 1 approximately 30 micrograms/mouse. It could not, however, suppress the established large metastasis of P388 leukemia. Lymph node cells isolated from the mice given bestatin i.p. at 1 and 30 microgram/mouse showed cytostatic activity against P388 leukemic cells in vitro than those from the untreated mice.

Animals↗
PubMed1981

Light microscopic localization of hepatitis B virus antigens in the human pancreas. Possibility of multiplication of hepatitis B virus in the human pancreas.

Hepatitis B virus has been considered to be strictly organotropic and to infect and multiply only the hepatocytes of humans and chimpanzees. The localization of hepatitis B surface antigen in extrahepatic tissues has been regarded as due to deposition or phagocytosis of hepatitis B surface antigen circulating in the blood. In the present study, however, we demonstrated hepatitis B virus antigens in the pancreases of autopsied subjects with hepatitis B surface antigenemia by Shikata's orcein stain, and immunoperoxidase, immunofluorescent studies; hepatitis B surface antigen and hepatitis B virus core antigen were localized within the cytoplasm of pancreatic acinar cells in 18 and 6 cases, respectively, out of 30 cases studied. In contrast, 25 autopsy cases with no hepatitis B surface antigenemia failed to stain hepatitis B surface antigen or hepatitis B core antigen in the pancreas and liver. Therefore, it may be reasonable to assume that hepatitis B virus can infect and replicate in the human pancreatic acinar cells; however no convincing hepatitis B virus-associated ultrastructures were detected in the present study. Although there were some cases demonstrating chronic inflammatory reaction or fatty necrosis, or both, in the pancreas with hepatitis B virus antigens, the causal relationship between these pathologic changes and hepatitis B virus infection awaits further clarification.

Adult↗
PubMed1981

Antitumor activity of 7-n-(p-hydroxyphenyl)-mitomycin C in experimental tumor systems.

The antitumor activity of 7-N-(p-hydroxyphenyl)-mitomycin C (M-83) was compared with that of mitomycin C (MMC) in rodent tumor systems. M-83 exhibited more potent activity than MMC against the ascitic form of lymphocytic leukemia P388 and fibrosarcoma Meth 1, and doses of over 5 mg/kg of M-83 (1/6 LD50) resulted in some 60-day survivors. The chemotherapeutic ratio (optimal dose/MED) of M-83 was around 64 and was estimated to be approximately 5 to 8 times higher than that of MMC. Upon intravenous administration, M-83 also gave a better survival and showed a higher chemotherapeutic ratio than MMC against intravenously implanted P388. M-83 inhibited the growth of solid form of sarcoma 180 to the same extent as MMC at an equivalent dose, but showed a higher safety margin than MMC. M-83 was as effective as MMC against Lewis lung carcinoma at dose levels giving the same degree of toxicity. In vitro studies on tumor growth inhibition demonstrated that the cytotoxic effects of M-83 against leukemia P388 and fibrosarcoma Meth 1 cells were similar to and stronger than those of MMC, respectively.

Animals↗
PubMed1981

Comparison of the hematologic toxicity of 7-N-(p-hydroxyphenyl),-mitomycin C and mitomycin C.

7-N-(p-Hydroxyphenyl)-mitomycin C (M-83), a new analog of mitomycin C (MMC) with equivalent or greater antitumor potencies against various experimental tumors, was investigated to determine its hematologic toxicity in mice. M-83 showed a significantly lower toxicity than MMC with respect to myelosuppression and leukopenia when compared at equivalent effective doses. In M-83-treated mice, the damage to the bone marrow was much milder at the nadir point and the recovery from myelosuppression to the normal level was faster as compared with that in the case of MMC. As a result, the number of white blood cells in the peripheral blood of the M-83-treated groups was considerably greater than that in the MMC-treated ones. These findings suggest that M-83 may be effective in clinical use.

Animals↗
PubMed1981

Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil.

A noncytotoxic dose of verapamil, a coronary vasodilator, enhances the cytotoxicity of vincristine (VCR) and vinblastine in P388 leukemia and its VCR-resistant subline, P388/VCR. When 2.2 to 6.6 microM verapamil was added along the VCR to the P388/VCR culture in vitro, VCR resistance was completely overcome. Verapamil in doses of 50 to 100 mg/kg administered daily for 10 days with VCR also enhances the chemotherapeutic effect of VCR in P388- and, especially, P388/VCR-bearing mice. When approximately 3 times the amount of VCR was given to a P388/VCR bearer as compared to a P388 bearer, VCR resistance was almost completely overcome in vivo with 50 to 100-mg/kg doses of verapamil. The amount of VCR incorporated into P388 cells was larger than that in P388/VCR cells. Verapamil (6.6 microM) enhanced the cellular level of VCR in P388 cells 2-fold and enhanced the level of VCR in P388/VCR cells 10-fold. The amount of VCR in P388/VCR cells reached the same level as that found in P388 cells. The overcoming of VCR resistance in vivo and in vitro could be explained by the effective accumulation of VCR by verapamil in P388/VCR cells mediated by the inhibition of a VCR efflux function of the cells, a mechanism which remains to be solved.

Animals↗
PubMed1981

Production of N4-succinyl-1-beta-D-arabinofuranosylcytosine, a novel metabolite of N4-behenoyl-1-beta-D-arabinofuranosylcytosine, in mice and its biological significance.

A novel metabolite was found in the urine and bile of mice given i.v. injections of N4-behenoyl-1-beta-D-arabinofuranosylcytosine (behenoyl-ara-C). Acid and alkaline hydrolysis of this metabolite resulted in the production of 1-beta-D-arabinofuranosylcytosine and succinic acid, as determined by thin-layer chromatography and high-performance liquid chromatography. Mass spectrometry identified this metabolite as N4-succinyl-1-beta-D-arabinofuranosylcytosine (succinyl-ara-C). This conclusion was supported by thin-layer chromatography and by the ultraviolet spectrum, upon which the characteristics of this metabolite agreed with those of succinyl-ara-C. Only a very small amount, if any, of this metabolite was found in the urine and bile of mice given injections of N4-stearoyl- or N4-palmitoyl-1-beta-D-arabinofuranosylcytosine, suggesting that behenoyl-ara-C was metabolized differently from the other two analogs. Comparison of the metabolites of behenoyl-ara-C, radiolabeled at different positions of the behenoyl-residue, suggested that behenoyl-ara-C was degraded by omega-oxidation and then by beta-oxidation, resulting in the production of succinyl-ara-C. This metabolite was more potent than behenoyl-ara-C in suppressing the in vitro proliferation of murine L1210 cells. The high therapeutic potency of behenoyl-ara-C in L1210-bearing mice may be ascribable to the contribution of succinyl-ara-C to the efficacy of behenoyl-ara-C, either by suppressing the proliferation of L1210 cells or by protecting 1-beta-D-arabinofuranosylcytosine, the possible eventual metabolite, from inactivation by deaminase.

Animals↗
PubMed1981

Membrane affinity and metabolism of N4-palmitoyl-1-beta-D-arabinofuranosylcytosine into cultured KB cells.

N4-Palmitoyl-1-beta-D-arabinofuranosylcytosine (N4-palmitoyl-ara-C), a lipophilic derivative of 1-beta-D-arabinofuranosylcytosine, possessed an affinity for KB cell plasma membrane. Approximately 15 to 25% of the drug incorporated into KB cells was retained in plasma membrane when the cells were treated with the drug for 1 to 32 hr at 10 microM, the concentration required for 50% inhibition of cell growth. Less than 5.3% of the drug was found in the plasma membrane when the cells were treated with 1-beta-D-arabinofuranosylcytosine. N4-Palmitoyl-ara-C in the membrane fraction cosedimented with plasma membrane in a sucrose density gradient at 4 degrees, indicating a close association between the drug and the membrane. The affinity of N4-palmitoyl-ara-C for plasma membrane probably contributes to the efficient uptake rate and the strong cytotoxic effect of N4-palmitoyl-ara-C reported previously. The metabolites of N4-palmitoyl-ara-C in KB cells, treated with the drug for 32 hr at the concentration required for 50% inhibition of cell growth (10 microM), were analyzed by diethylaminoethyl Sepharose CL-6B column chromatography and thin-layer and paper chromatography. This analysis showed that over 98% of the drug present in the KB cell was N4-palmitoyl-ara-C. The active metabolites, 1-beta-D-arabinofuranosylcytosine, 1-beta-D-arabinofuranosylcytosine 5'-monophosphate, N4-palmitoyl-1-beta-D-arabinofuranosylcytosine 5'-monophosphate, and 1-beta-D-arabinofuranosylcytosine 5'-triphosphate, were found in amounts of 0.41, 0.37, 0.17, and 0.05%, respectively, of the total drug found in the cells. Also found were the inactive metabolites 1-beta-D-arabinofuranosyluracil and 1-beta-D-arabinofuranosylcytosine diphosphate choline in amounts of 0.61 and 0.29%, respectively.

Animals↗
PubMed1981

Preferential action of liposome-entrapped 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea on lung metastasis of Lewis lung carcinoma as compared with the free drug.

Lipid vesicles entrapping a lipophilic antitumor agent, 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (MeCCNU), within the membrane phase were prepared and their antimetastatic activity was compared with that of free MeCCNU using intravenously inoculated Lewis lung carcinoma. It was found that the liposome preparation exhibited more potent inhibitory activity than the free drug on colony formation in the lung, when administered intravenously as well as intraperitoneally. Superior life-prolongation effect was also observed with liposome preparations as compared with the free drug in this system. However, the two forms of MeCCNU showed almost the same activity against not only Lewis lung carcinoma but also P388 leukemia inoculated subcutaneously and intraperitoneally, respectively. These results suggest that the superior effect of liposome-entrapped MeCCNU on lung metastasis might be due, at least in part, to preferential distribution of liposomes to the lung as compared with the free drug.

Animals↗
PubMed1980

Enhanced cytocidal action of methotrexate by conjugation to concanavalin A.

A methotrexate/concanavalin-A conjugate (MTX/Con-A) was prepared by covalent cross-linking. The extent of substitution was approximately 5 moles methotrexate (MTX) per mole concanavalin A (Con-A). Inhibition of dihydrofolate reductase by the conjugate was only marginal when compared to MTX. However, MTX/Con-A showed a 7- to 116 times higher cytocidal activity than MTX against cultured KB cells and various established cell lines from mouse colon adenocarcinomas 26 and 38, and Lewis lung carcinoma. The effect of MTX/Con-A was diminished when the conjugate was preincubated with alpha-methyl-D-mannoside, a specific binding sugar to Con-A. MTX/Con-A efficiently incorporated into cells and retained in them for longer periods of time than was MTX. The strong cytocidal action of the conjugate could be explained by the higher incorporation rate and the longer retention time of the conjugate in the cells.

Adenocarcinoma↗
PubMed1980

Suppression of Friend leukemia virus by Bacillus Calmette-Guérin and a streptococcal preparation, OK-432.

OK-432, a streptococcal preparation, and BCG effectively inhibited splenomegaly in Friend leukemia virus (FLV)-infected mice. Divided drug dosage resulted in stronger inhibition than single administration. When the second dose was fixed at the 3rd pre-infection day, the best timing for the first dose was approximately 30 days before infection. The optimal dosages were 100--600 KE/kg for OK-432 and 25--100 mg/kg for BCG. Transfer of peritoneal exudate cells (PEC) from immunomodulator-treated mice, but not PEC from untreated mice, conferred resistance against FLV which was highest when PEC were transferred 1 day before FLV infection. The transfer of PEC on the day of or one day after infection had no protective effect. Inactivation also occurred when FLV was incubated in the presence of PEC from immunomodulator-treated mice, however, no significant effect was observed for PEC from untreated mice.

Animals↗
PubMed1980

Review of experimental studies on nitrosourea derivatives in Japan.

Four antitumor nitrosourea derivatives under development in Japan are described. Among these, GANU and MCNU, having very similar structures to chlorozotocin, are water-soluble compounds, and CDL-7 and EBNU are rather insoluble in water. The latter two are before clinical trials, and like other nitrosourea derivatives, have a marked antitumor activity in mouse leukemia L1210. Though GANU and MCNU are in the stage of clinical studies, it seems premature to draw conclusions about them. Antitumor activity and pharmacologic studies on four nitrosourea compounds under development in Japan are reviewed. These compounds are: 1-(2-chloroethyl)-3-(beta-D-glucopyranosyl)-1-nitrosourea (GANU), 1-(2-chloroethyl)-3-(methyl-alpha-D-glucopyranos-6-yl)-1-nitrosourea (MCNU), DL-1(2-chloroethyl)-3-(hexahydro-2-oxo-azepin-3-yl)-1-nitrosourea (CDL-7), and 1,1'-ethylene-bis(1-nitrosourea) (EBNU).

Animals↗
PubMed1980

Inhibition of murine colon adenocarcinomas and Lewis lung carcinoma by 1-hexylcarbamoyl-5-fluorouracil.

1-Hexylcarbamoyl-5-fluorouracil (HCFU) and its parent compound 5-fluorouracil (5-FU) were tested PO for antitumor activity against mouse colon adenocarcinoma 26 (colon 26), colon adenocarcinoma 38 (colon 38), and Lewis lung carcinoma. The drugs were given orally at 2--4 days intervals for a total of ten doses. 5-FU was moderately active against colons 26 and 38 but not against Lewis lung carcinoma. In this treatment regimen the most impressive antitumor activity was obtained with HCFU against colons 26 and 38, especially colon 38 tumor. At 300 mg HCFU/kg, one out of seven mice inoculated with colon 26 and five out of ten mice inoculated with colon 38 became tumor-free. HCFU, however, was marginally effective in the prolongation of survival time of mice bearing Lewis lung carcinoma. 5-FU is approximately twice as active as HCFU against cultured cell lines from colon 26, colon 38, and Lewis lung carcinoma. Lewis lung carcinoma cells were most sensitive against HCFU, which is in contrast to the results obtained in the in vivo experiment. The IC50 value of HCFU against Lewis lung carcinoma cells was approximately half that against colon 26 and colon 38 cells. This higher sensitivity of Lewis lung cells against HCFU could be explained by the higher cellular uptake of the drug.

Adenocarcinoma↗
PubMed1980

Antitumor efficacies of aclacinomycin A by oral administration.

For the purpose of seeking a possible base for the oral clinical application of an anthracycline antibiotic, aclacinomycin A (ACM), ACM was given orally to the mice bearing Lewis lung carcinoma, colon adenocarcinomas 26 and 38, and compared with the effect of adriamycin (ADM). Oral administration of ACM at 5 or 10 mg/kg for 10 time suppressed the growth of Lewis lung carcinoma. There was no significant difference in survival times of the tumor-bearing mice given ACM orally at various dosages tested. ADM was not effective orally as long as the antitumor effect was examined at the dose levels tested. However, significant increase in the survival time of the mice implanted s.c. with colon adenocarcinoma 26 or 38 was noted for oral administration of ACM at 5-10 mg/kg for 10 times. Ths is, at 10 mg/kg of ACM, T/C% was 187% against colon 26 and 141% against colon 38, respectively. ADM, was not effective against these mouse tumors when given orally. Clinical application of ACM by oral administration, however, will need further studied including preclinical pharmacology, drug formulation and others.

Aclarubicin↗
PubMed1980

Growth inhibition of Lewis lung carcinoma by an inorganic dye, Ruthenium Red.

The growth of subcutaneously transplanted Lewis lung carcinoma in BDF1 mice was inhibited by an inorganic dye, Ruthenium Red. The mean volume of the tumors of the mice which were given Ruthenium Red by daily ip injection of 5 mg/kg on days 1 approximately 10 was 28 and 39% of that of the controls at days 18 and 23 after transplantation, respectively. The median survival time (MST) of the treated mice was 27.8 days while that of the control was 23.0 days. The higher MST (32.5 days) was obtained when the dye was given at 2.5 mg/kg for 1 approximately 20 days, although the tumor volume in this group of mice was 51% of that of the control at day 18.

Animals↗
PubMed1980

Antitumor activities of newly synthesized 5-carbamoyl-1 H-imidazol-4yl 1-adamantanecarboxylate and 5-carbamoyl-1H-imidazol-4yl piperonylate.

In synthetic studies on the chemical modification of the nucleoside antibiotic bredinin, two new derivatives, 5-carbamoyl-1H-imidazol-4-yl 1-adamantanecarboxylate and 5-carbamoyl-1H-imidazol-4-yl piperonylate, were found to possess a potent antitumor activity in several experimental tumor systems, even though bredinin itself shows only in vitro cytotoxicity and thus lacks therapeutic effectiveness. These two derivatives of bredinin exhibited antitumor activity against a wide variety of tumors, including leukemias L1210 and P388, Lewis lung carcinoma, B16 melanoma, Colon 26 and 38 adenocarcinomas. Ehrlich carcinoma, and Sarcoma 180. It is noteworthy that these agents showed good therapeutic effects not only against ascitic types of tumors but also against a number of slow-growing solid tumor lines, particularly the ascitic and solid forms of Ehrlich carcinoma. At their optimal doses, both compounds effected a complete cure of all or most of the mice treated. Although the mechanisms of action of these compounds remain unknown, they are able to suppress in vivo tumor growth, presumably by being slowly anabolized in vivo to an active form and inhibiting purine de novo synthesis as bredinin does.

Animals↗