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PR-000350, a novel hypoxic radiosensitizer, enhances tumor cell killing by promoting apoptosis preferentially in the S-phase fraction

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Abstract

PR-000350, a novel hypoxic radiosensitizer, is a 2-nitroimidazole nucleoside analog and has begun to be used for clinical cancer therapy. In this study, using U937 monoblastoid cells we investigated the mechanisms of enhanced cell killing by PR-000350. When cells were irradiated under an extremely hypoxic condition, the apoptotic rate was strongly suppressed. However, a remarkable increase in the DNA fragmentation rate as well as in the ladder formation was observed when hypoxic cells were irradiated in the presence of 5 mM PR-000350. DNA histograms of the PR-000350 treated group showed enhancement of the sub-G1 fraction and simultaneous suppression of the progression of the cell cycle from the S to G2/M phase at 4–8 h after X-irradiation, suggesting the importance of the S phase in the induction of apoptotic cell death. Flow cytometric and immunohistochemical analyses after BrdU labelling revealed that apoptotic cell death is induced mainly in the BrdU-positive cells. In addition, by using cell synchronization technique it was proved that the S phase is the most sensitive fraction to the radiosensitizing effect of PR-000350. These results suggest that PR-000350 strongly enhances tumor cell killing by promoting X-ray induced-apoptosis preferentially in the S-phase fraction. PR-000350 is a new type radiosensitizer and promise to provide an effective anti-cancer activity against hypoxic tumor cells that are resistant to the usual radiotherapy.

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Authors and Affiliations

  1. Pharmaceutical Research Laboratories, Pola R&D Laboratories, Pola Corporation, Kanagawa

    Y. Kuno

  2. Department of Microbiology, National Defense Medical College, Saitama, Japan

    N. Shinomiya

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  1. Y. Kuno
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  2. N. Shinomiya
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Kuno, Y., Shinomiya, N. PR-000350, a novel hypoxic radiosensitizer, enhances tumor cell killing by promoting apoptosis preferentially in the S-phase fraction. Apoptosis 5, 69–77 (2000). https://doi.org/10.1023/A:1009641827022

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