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Mechanism of tumor cell killing by HO-221, a novel antitumor compound

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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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Abbreviations

Ara-C :

cytosine arabinoside

ara-CTP :

1-β-d-arabinofuranosylcytosine-5′-triphosphate

ACNU :

nimustine

BCNU :

carmustine

HN2 :

nitrogen mustard

ACM :

actinomycin D

Cy-ic :

cyclohexyl isocyanate

ADM :

Adriamycin

DM :

daunomycin

CDDP :

cispratin

ddTTP :

2′,3′-deoxythymidine 5′-triphosphate

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Nakajima, T., Okamoto, T., Masuda, H. et al. Mechanism of tumor cell killing by HO-221, a novel antitumor compound. Cancer Chemother. Pharmacol. 27, 199–204 (1990). https://doi.org/10.1007/BF00685713

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