Cell Cycle Effects in Radiation Oncology
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Cells in the human body can be either dividing or nondividing. In order to undergo cell division, the cycling cells sequentially enter four different cell cycle phases: G1, S, G2, and M. It has long been known that cells in different cell cycle phases display different radiosensitivity. Cells in late S phase are usually most radioresistant and cells in M phase most radiosensitive. One of the classical four “R”s describing the rationale behind fractionated radiotherapy is based on such cell cycle differences, as fractionation allows tumor cells in a radioresistant cell cycle phase to “Redistribute” into more radiosensitive phases before the next fractions. Furthermore, some chemotherapeutic or targeted drugs applied in combination with radiation therapy can cause the tumor cells to accumulate in radioresistant or radiosensitive cell cycle phases, thereby altering the tumor radiosensitivity. It is also well known that radiation halts cell cycle progression through inducing arrest at the cell cycle checkpoints. Three major radiation-induced cell cycle checkpoints exist, in G1, S, and G2 phase. Because most irradiated tumor cells do not die before attempting to divide, the checkpoints are important to allow time for repair of the radiation damage. The G1 checkpoint is dependent on the tumor suppressor p53 and is often deficient or lacking in tumor cells. Tumor cells may therefore rely more on the S and G2 checkpoints for repair of radiation damage compared to normal cells. One strategy for obtaining tumor selective radiosensitization is thus to combine radiation with drugs that abrogate the G2 checkpoint.
KeywordsCell cycle checkpoints Radiosensitivity Cell cycle phase Checkpoint kinases ATR, Chk1 and Wee1
The Cell Cycle Phases and Radiosensitivity
Cell cycle phase-dependent differences in radiosensitivity are considered important during clinical radiotherapy. One of the rationales described by the original four R’s of fractionated radiotherapy is “Redistribution” of tumor cells into more radiosensitive cell cycle phases (Withers 1975b). If some tumor cells are in a radioresistant cell cycle phase at the time of the first fraction, they may move into a more radiosensitive phase before the next fraction. In this way, all cycling tumor cells are most likely hit in a radiosensitive phase during a whole course of fractionated radiotherapy. In contrast, redistribution will not apply to noncycling normal cells, which is one reason why fractionation helps to improve therapeutic gain.
Furthermore, cell cycle phase effects on radiosensitivity can be important when radiotherapy is combined with chemotherapy or new targeted drugs. Drugs administrated several hours or days prior to irradiation may alter the cell cycle phase distribution and thereby cause radioresistance or radiosensitivity. For instance, drugs causing the tumor cells to accumulate in mitosis before irradiation will likely cause radiosensitivity (Milas et al. 1999). On the other hand, there may be no radiosensitizing effect if such drugs are added after irradiation. In some cases the same drug can even cause either radiosensitivity or radioresistance, depending on the treatment timing and resulting cell cycle effects. For example, an inhibitor of Polo-Like Kinase 1 caused mitotic accumulation and radiosensitization in cancer cell lines when added 1 day prior to radiation treatment, while it caused prolonged G2 checkpoint arrest and radioresistance if added at the same time as radiation (Lund-Andersen et al. 2014).
Cell Cycle and Radiation-Induced Cell Death: Irradiated Tumor Cells Most Often Die After Attempting Mitosis
A classic paradigm in radiobiology is that radiation causes so-called mitotic death (also called mitosis-linked death or mitotic catastrophe) (Hall and Giaccia 2006; Wouters 2009). This means that radiation does not kill the tumor cells right away but that cell death occurs at some point after the first mitosis following irradiation. The irradiated cells may undergo one, two, or a few divisions before they die hours or days later (Forrester et al. 1999).
Mitotic death is the most common way of radiation-induced cell death for all solid tumors and most of hematopoietic tumors. However, for some hematopoietic tumors and a few normal cell types, such as normal lymphocytes and thymocytes, radiation can induce rapid death in interphase (G1, S, and G2 phases) prior to mitosis. In the latter case, apoptosis is triggered due to activation of radiation-induced signaling cascades (Wouters 2009).
Cell Cycle Checkpoints Induced by Radiation
The cell cycle checkpoints are important to provide time for DNA repair before cells are reaching mitosis. As discussed above, irradiated cancer cells often die via mitotic death. It is therefore critical whether or not the DNA damage is repaired prior to the first mitosis after radiation. Some repair pathways, such as HR and slow versions of Non-Homologous-End-Joining, take many hours to complete (Iliakis et al. 2004; Jeggo et al. 2011), and a few hours arrest at the cell cycle checkpoints can therefore make a difference in preventing mitotic death. Of note, arrest at the cell cycle checkpoints can also sometimes be permanent, thereby being a way of causing cell inactivation through senescence. Particularly, in normal fibroblasts radiation can induce permanent p53-dependent G1 arrest, which contributes to the cell inactivation of fibroblasts measured in clonogenic survival assays (Li et al. 1995; Tsang et al. 1995; Linke et al. 1997). However, after irradiation of fibroblasts with low doses such as 2 Gy, only a fraction of the cells will arrest permanently. A transient G1 arrest is observed in the remaining fraction, likely contributing to DNA repair.
Abrogation of the G2 Checkpoint as a Strategy for Tumor Radiosensitization
In conclusion, variation in tumor radiosensitivity between different cell cycle phases is one of the rationales behind fractionation in radiation therapy. Such variation in radiosensitivity can be important when radiotherapy is combined with drugs that alter the cell cycle phase distribution. Furthermore, the induction of cell cycle checkpoints in G1, S, and G2 phases is a major cellular effect of radiation. Notably, differences in the G1 checkpoint between normal and tumor cells may be exploited to obtain tumor-selective radiosensitization through G2 checkpoint abrogation. For this purpose, inhibitors of the ATR, Chk1, and Wee1 checkpoint kinases are currently being tested in combination with radiotherapy in preclinical and clinical studies.
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