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Biomedical subjects

T Tsuruo

Publications and source records attributed to T Tsuruo.

At least 505 records · Page 28Linked to original sources
PubMed1981

Enhancement of vinblastine-induced cytotoxicity by lysolecithin and phosphatidylinositol.

Vinblastine inhibited the growth of cultured KB cells 3 days after drug treatment by 55% and 67% at 2.7 ng/ml and 3.5 ng/ml of the medium, respectively. Lysolecithin and phosphatidylinositol showed only a marginal inhibitory effect on the growth of KB cells at respective concentrations of 35-125 microgram/ml and 50-150 microgram/ml of the medium. Lysolecithin, however, enhanced the cytotoxicity of vinblastine. Depending upon the concentrations of lysolecithin (35-125 microgram/ml), the growth of KB cells was inhibited by 60-91% and 86-98% at respective vinblastine concentrations of 2.7 ng/ml and 3.5 ng/ml. Enhancement of vinblastine-induced cytotoxicity also occurred similarly for phosphatidylinositol. The mechanism could be explained partly by an elevated amount of intracellular vinblastine. Other possible mechanisms can only be speculated.

Cells, Cultured↗
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

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

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

Differences in drug sensitivity among tumor cells from parental tumors, selected variants, and spontaneous metastases.

Eradication of drug-resistant tumor foci is essential to the successful treatment of metastasis with chemotherapeutic agents. In this study, we examined the in vitro sensitivity to a variety of chemotherapeutic agents of tumor cells from parental tumors, from their in vitro-cloned populations, and from their spontaneous metastases. Three murine tumors were studied: the B16 melanoma; the K-1735 melanoma; and the UV-2237 fibrosarcoma. In addition, we also examined the in vitro drug sensitivity of cells from the A-375 human melanoma and its various subpopulations. The drugs used in these studies were Adriamycin, 4'-(9-acridinylamino)methanesulfon-m-anisidine, bleomycin, 5-)3,3-dimethyl-1-triazeno)imidazole-4-carboxamide, vincristine, and vindesine. The growth-inhibiting activity of the drugs was recorded in values which were derived from plotting the logarithm of the drug concentration versus the growth rate (percentage of control) of the treated cells and which determined the molar concentration of drugs necessary to reduce doubling by 50%. Our results demonstrate that differences in drug response exist among cells populating a parental tumor (in vitro cloned), between the parental line and its metastatic subpopulations (in vivo-selected lines), and among the various spontaneous metastases. These extensive differences in drug sensitivity could have profound implications for the treatment of metastases with cytotoxic drugs.

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↗
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

Purification and properties of a DNA ligase from a soluble DNA replication complex.

A DNA ligase has been purified from a subnuclear soluble replication complex isolated from adenovirus type 2-infected human KB cells. DNA ligase activity could not be demonstrated using an exogenous template until the complex was dissociated, suggesting that the ligase activity may be a component of the complex. The purified enzyme was free of endonuclease, exonuclease, 5'-nucleotidase, and phosphatase activities, and had a molecular weight of 105 000, as estimated by sedimentation in a glycerol gradient. The ligase requires ATP and a divalent cation for activity. The optimum of the reaction is at pH 7.8 in 50--100 mM Tris-HCl buffer and 10--20 mM MgCl2. Monovalent salts greatly stimulate ligase activity and the optimum was found at 150 mM. The reaction is very sensitive to high temperature; maximum activity was observed at 25--30 degrees C. ATP is the sole required cofactor and NAD, dATP and GTP could not replace the requirement for ATP. The Km for ATP is 60 microM. The Km for DNA is 250 microgram/ml or 1.6 nmol of terminal phosphate/ml and thus the enzyme shows relatively weak affinity for exogenous DNA. The maximum conversion of 32P into a phosphatase-resistant form is approximately 1.3% of the total, whereas T4 ligase, under the same conditions, can convert more than 25% of phosphate into a resistant form.

Adenoviruses, Human↗
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

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

Lymph node metastasis and effects of 1-beta-D-arabinofuranosylcytosine, 5-fluorouracil, and their lipophilic derivatives in an experimental model system using P388 leukemia.

Mouse P388 leukemic cells inoculated into the right forefootpad metastasized primarily to the right axillary lymph node. No significant metastasis to other lymph nodes or organs was detected on Day 12 after the inoculation of 10(6) P388 cells in the forefootpad, except that a lesser extent of metastasis was observed in some cases in the right inguinal lymph node, liver, and spleen. A quantitative estimation of metastasis in the axillary lymph node was accomplished by transferring the lymph node i.p. to the recipient mice (bioassay method). The metastasis of P388 cells to the axillary lymph node occurred linearly depending on the elapse of time after inoculation. In studying the chemotherapeutic effect on lymph node metastasis, two experimental models were established. Model 1, 10(6) P388 cells were inoculated into the right forefootpad, and drug was administered thereafter. The right axillary lymph node was removed on Day 8, and the extent of inhibition of lymph node metastasis was estimated by the bioassay method. In Model 2, P388 cells were inoculated, and the right forelimb including original tumor was amputated on Day 6 when the metastasis had already been established. The drug was given thereafter, and the extent of inhibition of metastasis was estimated on Day 12 by the bioassay method. In this experimental system, a lipophilic derivative N4-behenoyl-1-beta-D-arabinofuranosylcytosine was more effective than its parent compound 1-beta-D-arabinofuranosylcytosine; however, 5-fluorouracil was found to be more potent than its lipophilic derivative ftorafur for the inhibition of lymph node metastasis, suggesting an existence of various pharmacokinetic factors for the inhibition of lymph node metastasis.

Animals↗
PubMed1978

An endodeoxyribonuclease of human KB cells. Purification and properties of the enzyme.

An endodeoxyribonuclease has been purified 750-fold from human KB cells. The purified endonuclease requires Mg2+ for maximum activity: Mn2+ was less than half as active and Ca2+ inhibited the reaction. The optimum pH is 8.8 in Tris-HCl and the optimum buffer concentration is 10 mM. KCl (and NaCl), --SH-reacting reagents, and tRNA strongly inhibit the reaction. An apparent molecular weight of 54,000 was determined by sedimentation in a glycerol gradient. The purified endonuclease cleaved native, double-stranded adenovirus 2 DNA, and the reaction proceeded stepwise during the initial stage of degradation by cleavage of the DNA substrate in half, then in half again, etc. At longer digestion times, single strand scissions were detected. RNA was not a substrate for the enzyme. Poly(dG) . poly(dC) was susceptible but poly(dA) . poly(dT) was resistant to degradation. Hydrolysis of adenovirus 2 DNA yielded double-stranded polynucleotides containing 5'-phosphoryl and 3'-hydroxyl termini with short, single-stranded regions presumably at the ends. More than 50% of the product of a limit digest had a chain length greater than 35 to 40 nucleotides. Analysis of the 5' and 3' end groups of the digestion products indicated a preference for the site of the enzymatic cleavage; thymidylic acid residues were present at the 5' end and deoxyguanosine residues at the 3' end, each with a frequency of 40 to 50%.

Cell Line↗