PR-000350, a novel hypoxic radiosensitizer, enhances tumor cell killing by promoting apoptosis preferentially in the S-phase fraction.
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.
Kuno
Y
Y
Pharmaceutical Research Laboratories, Pola  Corporation, Kanagawa, Japan.
Shinomiya
N
N
D000693:Anaerobiosis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001973:Bromodeoxyuridine / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D016196:S Phase / Q000187:drug effects*; D020298:U937 Cells; D014964:X-Ray Therapy / Q000379:methods
C422410:3-((2-nitroimidazol-1-yl)methoxy)butane-1,2-4-triol; D000970:Antineoplastic Agents; D007093:Imidazoles; D011838:Radiation-Sensitizing Agents; D001973:Bromodeoxyuridine