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Cancer Chemotherapy and Pharmacology

, Volume 27, Issue 3, pp 199–204 | Cite as

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

  • Tsunetaka Nakajima
  • Tadao Okamoto
  • Hirotoshi Masuda
  • Masahiro Watanabe
  • Kazumasa Yokoyama
  • Nobutoshi Yamada
  • Shigeru Tsukagoshi
  • Tetsuo Taguchi
Original Articles Mechanism of Action, HO-221, DNA Polymerase

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.

Keywords

Anthracycline Polymerase Activity Tumor Cell Killing Aphidicolin Reverse Transcriptase Activity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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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Copyright information

© Springer-Verlag 1990

Authors and Affiliations

  • Tsunetaka Nakajima
    • 1
  • Tadao Okamoto
    • 1
  • Hirotoshi Masuda
    • 1
  • Masahiro Watanabe
    • 1
  • Kazumasa Yokoyama
    • 1
  • Nobutoshi Yamada
    • 2
  • Shigeru Tsukagoshi
    • 3
  • Tetsuo Taguchi
    • 4
  1. 1.Research DivisionThe Green Cross CorporationHirakata, OsakaJapan
  2. 2.Research DivisionIshihara Sangyo Kaisha, LTD.KusatsuJapan
  3. 3.Cancer Chemotherapy Center, Cancer InstituteJapanese Foundation for Cancer ResearchTokyoJapan
  4. 4.Department of Oncologic Surgery, Research Institute for Microbial DiseasesOsaka UniversitySuita, OsakaJapan

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