The reversibility of cancer radioresistance: a novel potential way to identify factors contributing to tumor radioresistance

To understand the molecular mechanisms responsible for radioresistance in cancer cells, we previously established clinically relevant radioresistant (CRR) cell lines from several human cancer cell lines. These CRR cells proliferate even under exposure to 2 Gy/day of X-rays for more than 30 days, which is a standard protocol for tumor radiotherapy. CRR cells received 2 Gy/day of X-rays to maintain their radioresistance (maintenance irradiation; MI). Interestingly, CRR cells that did not receive MI for more than a year lost their radioresistance, indicating that radiation-induced radioresistance is reversible. We designated these CRR-NoIR cells. Karyotyping of the parental and CRR cells revealed that the chromosomal composition of CRR cells is quite different from that of the parental cells. However, CRR and CRR-NoIR cells were more similar compared with the parental cells because CRR cells repair X-ray-induced DNA damage with higher fidelity. To identify the factor(s) involved in tumor radioresistance, previously published studies including ours have compared radioresistant cells to parental cells. In this review, we conclude that a comparison between CRR and CRR-NoIR cells, rather than parental cells, is the best way to identify factors involved in tumor radioresistance.