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  • 1
    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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  • 2
    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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  • 3
    ISSN: 1432-0843
    Keywords: IST-622 ; Chartreusin derivative ; Orally active antitumor agent
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The antitumor effects of 6-O-(3-ethoxypropionyl)-3′,4′-O-exo-benzylidenechartreusin (IST-622), a new synthetic derivative of chartreusin (CT), were investigated. Following oral administration, IST-622 showed marked antitumor effects against various mouse tumors such as P388 and L 1210 leukemias, B 16 melanoma, Lewis lung carcinoma, Colon 26 and Colon 38 adenocarcinomas, and M5076 reticulum-cell sarcoma. The best antitumor effects were obtained by five intermittent treatments given every 4 days. In addition, IST-622 showed a significant growth-inhibitory effect against two human tumor xenografts, a large-cell lung cancer (Lu-116) and a gastric adenocarcinoma (St-4), among the seven lines tested. IST-622, which was rapidly metabolized into 3′,4′-O-exo-benzylidenechartreusin (A-132) and not into CT in vivo or in culture medium, exhibited remarkable growth-inhibitory activity against P388 leukemia in vitro, its 50% growth-inhibitory concentration (IC50) being over 20-fold lower than that of CT. IST-622 showed an in vivo antitumor effect superior to that of authentic A-132, possibly resulting from a higher absorption ratio of IST-622 through the gastrointestinal tract. IST-622 is now under clinical phase I study in Japan.
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  • 4
    ISSN: 1432-0843
    Keywords: Key words: IST-622 – Chartreusin derivative – Orally active antitumor agent
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. The antitumor effects of 6-O-(3-ethoxypro- pionyl)-3′,4′-O-exo-benzylidenechartreusin (IST-622), a new synthetic derivative of chartreusin (CT), were investigated. Following oral administration, IST-622 showed marked antitumor effects against various mouse tumors such as P388 and L1210 leukemias, B16 melanoma, Lewis lung carcinoma, Colon 26 and Colon 38 adenocarcinomas, and M5076 reticulum-cell sarcoma. The best antitumor effects were obtained by five intermittent treatments given every 4 days. In addition, IST-622 showed a significant growth-inhibitory effect against two human tumor xenografts, a large-cell lung cancer (Lu-116) and a gastric adenocarcinoma (St-4), among the seven lines tested. IST-622, which was rapidly metabolized into 3′,4′-O-exo-benzylidenechartreusin (A-132) and not into CT in vivo or in culture medium, exhibited remarkable growth-inhibitory activity against P388 leukemia in vitro, its 50% growth-inhibitory concentration (IC50) being over 20-fold lower than that of CT. IST-622 showed an in vivo antitumor effect superior to that of authentic A-132, possibly resulting from a higher absorption ratio of IST-622 through the gastrointestinal tract. IST-622 is now under clinical phase I study in Japan.
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  • 5
    ISSN: 1432-0843
    Keywords: Key words 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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  • 6
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A novel antitumor compound,N-[4-(5-bromo-2-pyrimidinyloxy)-3-chlorophenyl]-N′-(2-nitrobenzoyl) urea (HO-221) was evaluated for its antitumor activity in experimental tumor models. HO-221 preparation was given orally to tumor-bearing animals. The compound exhibited significant effects against various tumors such as P388 and L1210 leukemias; M5076 reticulum-cell sarcoma; colon 38 carcinoma; human xenografts MX-1, LX-1, GA-1, and Co-1; Lewis lung carcinoma; sarcoma 180; and Walker 256 carcinosarcoma and was especially effective against solid tumors. However, its effect on murine B16 melanoma was moderate. Intermittent administration of HO-221 produced better results. The effects of HO-221 on human tumor xenografts were compared with those of other antitumor agents. HO-221 showed activity against LX-1 lung and Co-1 gastrointestinal tumor and was also effective against advanced-stage L1210 leukemia and Lewis lung carcinoma. Furthermore, the effect of HO-221 on drug-resistant tumors was examined using murine leukemias L1210 and P388. It showed no cross-resistance with the known antitumor agents Adriamycin (ADM), daunomycin (DM), vincristine (VCR), mitomycin C (MMC), cisplatin (CDDP), 5-fluorouracil (5-FU), cytosine arabinoside (Ara-C), methotrexate (MTX), cyclophosphamide (CPA), or carboquone (CQ), and collateral sensitivity to HO-221 was found in MMC-, CDDP-, and CPA-resistant sublines. HO-221 exhibits significant reproducible, broadspectrum antitumor activity against experimental tumors as well as human neoplasms.
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