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  • 1
    ISSN: 1573-7276
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Metastatic tumor burden in the lung of C57BL/6 or BDF1 mice was quantitated by measuring DNA polymerase a activity in the lung of tumor-bearing animals. DNA polymerase activity in the lung increased time-dependently following the inoculation of Lewis lung carcinoma (s.c.) or B16 melanoma variant B16–B2 (i.v.). In the Lewis lung carcinoma system, the number of metastatic modules and the weight of lung also increased time-dependently. Results from the B16 melanoma showed that the increase in lung nodules occurred 10 to 20 days after i.v. inoculation of tumor cells. DNA polymerase activity increased significantly during this period. Because the lung nodules were very small there was no obvious concomitant increase in lung weight. Since no significant infiltration of host cells was observed in the lung in response to metastatic foci, the rise in DNA polymerase activity should be due to tumor cells and not to infiltrating host cells. When the metastasis of Lewis lung carcinoma was inhibited by adriamycin and cyclophosphamide, decrease in DNA polymerase activity in the lung occurred. These results indicate that the degree of tumor metastasis can be quantitated by measuring DNA polymerase activity.
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  • 2
    ISSN: 1573-7276
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effects of lung tissue extract on the cell growth of eight colon 26 tumor clones, four highly and four poorly lung-colonizing clones, were examinedin vitro. Addition of lung extract to serum-free medium stimulated the growth of all four of the highly lung-colonizing clones and one of the poorly lung-colonizing clones, but it had minimal effect on the other three poorly lung-colonizing clones. These results indicate that the lung extract contains a growth stimulating activity; it selectively stimulated some of the colon 26 clones including highly lung-colonizing ones. The growth stimulating activity was not dialyzable, was partially destroyed by heating at 56
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  • 3
    ISSN: 1573-7276
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A metastatic tumor population was isolated in BALB/c mice during routine s.c. passage of the colon 26 adenocarcinoma. The tumor metastasized to lymph nodes, liver, spleen, ovary and kidney. A primary culture established from the s.c. growing tumor was composed of both adherent and nonadherent cells. These two cell types were successfully separated from the primary culture and designated CMS (suspension cells) and CMA (adherent cells). The CMS and CMA cell lines are morphologically distinct in culture; however both formed similar histopathologic tumors when inoculated s.c. Furthermore, both tumor lines showed identical metastatic patterns in BALB/c mice with involvement of lymph node, liver, spleen, ovary and kidney. CMS and CMA expressed T-antigen as revealed by FITC-labeled-anti-Thy 1.2 antibody. Chromosome analysis and morphologic studies by light and electron microscopy indicated that the present metastatic lines have no relationship with the colon 26 adenocarcinoma and seem to be non-thymic T-cell lymphosarcomas which developed spontaneously in BALB/c mice.
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  • 4
    ISSN: 1520-5126
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
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  • 5
    ISSN: 0025-116X
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Physics
    Notes: Polymeric conjugates of adriamycin (ADR) (2) or daunomycin (DM) (3) were synthesized by reaction of the drugs with the copolymer of divinyl ether and maleic anyhdride (DIVEMA) (1). The content of ADR moieties in the DIVEMA conjugate (4) could be varied depending on the reaction conditions up to 35,8 wt.-%. Considering the low toxicity and the high possibility of renal excretion, DIVEMA with M̄w of 7000 and M̄w/M̄n = 1,6 was used for the conjugation. The rate of drug release from the conjugate was determined under physiological conditions by reversed phase HPLC. Within 14 days only 15% of the attached ADR was released from conjugate 4. The antitumor activity of the conjugates was tested in vitro and in vivo against mouse P388 leukemia. Conjugate 4 proved to be 28 times less active than ADR in vitro, which could be explained from the slow drug-release. On the contrary 50% of the leukemic mice treated by 4 survived more than 60 days, whereas no mice given ADR alone or the admixture of ADR and DIVEMA survived 30 days. An antitumor activity of the polymeric conjugate better than that of the free drug was also observed in vivo with DM. Such a polymeric effect can be attributed either to the change in body distribution, the difference in pharmacokinetics, or the slow drugrelease.
    Additional Material: 6 Ill.
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  • 6
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The mechanism of tumor cell killing by HO-221, a novel benzoylphenylurea derivative that shows broad-spectrum antitumor activities, was studied. HO-221 strongly inhibited the activity of mammalian DNA polymerase α but not that of DNA polymerases β or γ. The inhibition was equivalent to that induced by aphidicolin and ara-CTP, which were selective inhibitors of the enzyme. Furthermore, the inhibition by HO-221 of DNA polymerase α was found to be non-competitive with respect to dCTP as a substrate, unlike that induced by aphidicolin and ara-CTP. The inhibition was reduced the addition of an excess of DNA polymerase α but not by excess amounts of activated DNA as a template primer. These results suggest that HO-221 inhibits the activity of DNA polymerase α by direct interaction with the enzyme in contrast to the impairment of template activity through intercalation into DNA induced by anthracycline compounds. On the other hand, HO-221 showed almost no effect on RNA polymerase activity, the reverse transcriptase activity of avian myeloblastosis virus or protein synthesis in a cell-free system. The flow-cytometry analysis revealed that HO-221 accumulated HL-60 cells in G1-S phases at a low concentration but increased the number of cells in the G1 phase at a higher concentration, stopping cell-cycle progression. The results suggest a correlation between cell-cycle progression and inhibition by HO-221 of DNA polymerase α, which plays a role in DNA replication during the S phase in living cells.
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  • 7
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A novel antitumor compound,N-β-dimethylaminoethyl 9-carboxy-5-hydroxy-10-methoxybenzo[a]-phenazine-6-carboxamide sodium salt (NC-190), has potent antitumor activity against in vivo and in vitro tumor models. In this study, we evaluated the cell-cycle effect of NC-190 on cultured HeLa S3 cells using DNA/bromodeoxyuridine(BrdU) bivariate flow-cytometric analysis. Continuous treatment with NC-190 for 72 h inhibited the growth of cultured Hela S3 cells in a concentration-dependent manner. Its 50% growth-inhibitory concentration (IC50) was 0.039 μg/ml (0.085 μM). The cell-cycle effects of NC-190 were dependent on the drug concentration and the treatment period. Continuous treatment with a low concentration (0.1 μg/ml) of NC-190 inhibited cell-cycle progression from the G2 to the M phase, resulting in G2 accumulation. With increasing concentration, NC-190 delayed cell-cycle traverse in the S and G2 phases. At a higher (10 μg/ml) concentration of NC-190, cell-cycle traverse was prevented in the G1, S, and G2 phases. Under such conditions, NC-190 increased the numbers of S0-phase cells (the cells with DNA content corresponding to that of S-phase cells, but without BrdU incorporation). Treatment for 2 h with NC-190 at 10 μg/ml induced the accumulation of cells in the G2 phase, and cell debris was observed at 48 and 72 h after drug treatment. During this time, the proportion of cells in the S0 phase increased up to 19.2%. The colcemid-induced mitotic cell accumulation was delayed by NC-190 at a concentration of 0.1 μg/ml at 4 h after the addition of the drugs. The addition of higher concentrations (1 and 10 μg/ml) of NC-190 inhibited the increase in the mitotic fraction completely. These results indicate that the mechanism involved in the G2 arrest and the increment of S0-phase cells caused by NC-190 is associated with this compound-induced cell death.
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  • 8
    ISSN: 1432-0843
    Keywords: HO-221 ; Benzoylphenylurea derivative ; Antimicrotubule effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The antitumor action of HO-221, a novel benzoylphenylurea derivative, was studied. The in vitro cytotoxic strength of HO-221 was investigated, as measured by IC50 values, compared with those of other drugs with different action mechanisms, using Chinese hamster lung (CHL) cells, mouse leukemia L1210 cells and human promyelocytic leukemia HL-60 cells. Morphological alterations following treatment were observed under a phase contrast microscope, and the mitotic index was determined at regular intervals to check for accumulation of metaphase cells. HO-221 was found to have a very strong toxic effect on all cell types, equal to that of the spindle poisons used as controls. HO-221 also produced the same specific morphological changes as the spindle poisons, with a significant accumulation of metaphase cells. A chromosome analysis of treated cells showed that HO-221 frequently induced polyploid and aneuploid cells, but without accompanying chromosome-breaking activity. An in vivo mouse bone marrow micronucleus assay was also carried out. The assay allowed the in vivo identification of a chromosome breaker or a spindle poison through the measurement of the relative sizes of micronuclei produced and erythrocytes. HO-221 was found frequently to induce relatively large micronuclei, an action regarded as specific to spindle poisons. It was thus demonstrated that HO-221 acts as a spindle poison both in vitro and in vivo. In order to investigate the mechanism of this action, a study of tubulin assembly using purified calf brain tubulin was carried out, which demonstrated clearly that HO-221 inhibits microtubule assembly. A detailed investigation of the action mechanism of HO-221 as a spindle poison is now called for.
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  • 9
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We studied bioavailability, treatment schedule dependence, and therapeutic efficacy of orally administered MST-16, a novel derivative of bis(2,6-dioxopiperazine), against murine tumors and human tumor xenografts. The rate of its intestinal absorption was about 50%, and it was immediately metabolized to its parent compound, ICRF-154. Therapeutic efficacy of MST-16 was heavily dependent on the treatment schedule: 9 daily oral administrations and treatment every 4 h on day 1 only were much more effective against s.c.-implanted L1210 leukemia than a single dose or five daily administrations giving the same total dose. Orally administered MST-16 showed potent lifeprolonging effects (196%, 219% and 148%) in mice inoculated i.p. with P388, L1210 leukemia, and C-26 colon adenocarcinoma, respectively, but had no effect on B16 melanoma inoculated in the same way. MST-16 inhibited more than 80% growth of Lewis lung carcinoma, B16 melanoma, and C-38 colon adenocarcinoma implanted s.c., but had only a minor effect on M5076 fibrosarcoma. Lung metastasis of Lewis lung carcinoma was also effectively suppressed. Furthermore, MST-16 significantly inhibited growth of human colon, lung and breast cancers implanted s.c. in nude mice. We also made a kinetic analysis of the in vitro cell-killing effect by ICRF-154, the active form of MST-16 in vivo. It demonstrated a cell cycle phase-specific and time-dependent action, providing a reasonable explanation for the schedule-dependent therapeutic effect of MST-16.
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  • 10
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Verapamil, a calcium antagonist, inhibited both experimental (IV inoculation of tumor cells) and spontaneous metastasis (SC inoculation) of the highly metastatic B16 melanoma and colon adenocarcinoma 26 cell lines. Verapamil treatment resulted in a maximum 80% inhibition of metastases, the degree of inhibition varying among the different metastatic systems. Verapamil inhibited platelet aggregation induced by these tumor cell lines, the patterns of inhibition being different for B16 melanoma and colon adenocarcinoma. The inhibition of platelet aggregation induced by tumor cells is proposed as a mechanism by which the calcium antagonist exerts its antime-tastatic effect. These results, together with our previous findings that calcium antagonists can increase the cytotoxicity of drugs in tumor cells with induced or inherent drug resistance by inhibiting outward transport of the drug, indicate that calcium antagonists have potential as a new class of adjuvant agents in the field of cancer chemotherapy.
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