Schedule-dependent interaction between anticancer treatments

Science  11 Mar 2016:
Vol. 351, Issue 6278, pp. 1204-1208
DOI: 10.1126/science.aac5610

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Timing the attack on cancer cells

Cell regulatory systems have dynamic properties that will need to be taken into account when planning therapeutic strategies. Chen et al. found that the timing of a radiation treatment of human breast cancer–derived cells in culture determined whether cell survival was enhanced or reduced. Depletion of the oncogene product MDMX caused an initial burst of expression of the tumor suppressor protein p53 within the first 24 hours, and then oscillations of lower amplitude. When the radiation treatment coincided with the first phase, 95% of the cells died, but if radiation was applied in the second phase, fewer than 20% of the cells died.

Science, this issue p. 1204


The oncogene MDMX is overexpressed in many cancers, leading to suppression of the tumor suppressor p53. Inhibitors of the oncogene product MDMX therefore might help reactivate p53 and enhance the efficacy of DNA-damaging drugs. However, we currently lack a quantitative understanding of how MDMX inhibition affects the p53 signaling pathway and cell sensitivity to DNA damage. Live cell imaging showed that MDMX depletion triggered two distinct phases of p53 accumulation in single cells: an initial postmitotic pulse, followed by low-amplitude oscillations. The response to DNA damage was sharply different in these two phases; in the first phase, MDMX depletion was synergistic with DNA damage in causing cell death, whereas in the second phase, depletion of MDMX inhibited cell death. Thus a quantitative understanding of signal dynamics and cellular states is important for designing an optimal schedule of dual-drug administration.

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