☢️Radiobiology Unit 9 – Cell Cycle Effects and Radiosensitivity

Key Concepts in Cell Cycle and Radiosensitivity

• Cell cycle consists of a series of events that lead to cell division and replication
• Radiosensitivity refers to the susceptibility of cells to damage from ionizing radiation
• Different phases of the cell cycle exhibit varying levels of radiosensitivity
• DNA damage and repair mechanisms play a crucial role in determining cell survival after radiation exposure
• Cell survival curves and mathematical models help predict the response of cells to radiation
• Fractionation of radiation doses can exploit differences in radiosensitivity between normal and tumor cells
• Understanding cell cycle effects and radiosensitivity has significant clinical implications in radiotherapy

Phases of the Cell Cycle

• The cell cycle is divided into four main phases: G1, S, G2, and M
  • G1 phase involves cell growth and preparation for DNA synthesis
  • S phase is characterized by DNA replication and synthesis of new genetic material
  • G2 phase includes further cell growth and preparation for mitosis
  • M phase encompasses mitosis (nuclear division) and cytokinesis (cell division)
• Cells can also enter a quiescent state called G0 when not actively dividing
• Progression through the cell cycle is regulated by various checkpoints and signaling pathways
• Cyclins and cyclin-dependent kinases (CDKs) are key regulators of cell cycle progression
• Duration of each phase varies depending on the cell type and environmental factors

DNA Damage and Repair Mechanisms

• Ionizing radiation can cause various types of DNA damage, including single-strand breaks (SSBs), double-strand breaks (DSBs), and base modifications
• DSBs are considered the most lethal form of DNA damage and are the primary cause of radiation-induced cell death
• Cells have evolved several DNA repair mechanisms to maintain genomic integrity
  • Base excision repair (BER) corrects small base modifications and SSBs
  • Nucleotide excision repair (NER) removes bulky DNA lesions and helix-distorting damage
  • Homologous recombination (HR) and non-homologous end joining (NHEJ) are the main pathways for repairing DSBs
• The efficiency and fidelity of DNA repair mechanisms influence cell survival and the risk of mutations
• Defects in DNA repair genes can lead to increased radiosensitivity and predisposition to cancer

Radiosensitivity Variations Across Cell Cycle

• Radiosensitivity varies significantly throughout the cell cycle
• Cells in the M and G2 phases are most sensitive to radiation, while cells in the late S phase are the most resistant
  • M phase cells have condensed chromatin and are unable to repair DNA damage effectively
  • G2 phase cells have a short time to repair damage before entering mitosis
  • Late S phase cells have replicated DNA, providing a template for repair through HR
• Cells in the G1 and early S phases exhibit intermediate radiosensitivity
• The differences in radiosensitivity across the cell cycle are exploited in fractionated radiotherapy to maximize tumor cell killing while minimizing damage to normal tissues

Cell Survival Curves and Models

• Cell survival curves depict the relationship between radiation dose and the fraction of surviving cells
• The linear-quadratic (LQ) model is widely used to describe cell survival curves
  • The LQ model assumes that cell killing is a combination of two components: a linear (α) and a quadratic (β) component
  • The α component represents irreparable lethal damage, while the β component represents sublethal damage that can be repaired
• The α/β ratio is a measure of the relative contribution of the linear and quadratic components to cell killing
  • Tissues with a high α/β ratio (e.g., tumors) are more sensitive to changes in fraction size
  • Tissues with a low α/β ratio (e.g., normal tissues) are more sensitive to changes in total dose
• Other models, such as the single-hit multi-target model and the repair-misrepair model, have also been proposed to describe cell survival curves

Fractionation and Its Effects

• Fractionation involves dividing a total radiation dose into smaller, multiple doses delivered over time
• Fractionation allows normal tissues to recover between doses while maintaining tumor cell killing
• The four R's of radiobiology explain the benefits of fractionation:
  • Repair of sublethal damage in normal tissues
  • Reassortment of cells into more radiosensitive phases of the cell cycle
  • Reoxygenation of hypoxic tumor cells, making them more radiosensitive
  • Repopulation of normal tissues between fractions
• Hyperfractionation involves delivering smaller doses more frequently, while hypofractionation involves larger doses delivered less frequently
• The choice of fractionation scheme depends on the tumor type, location, and surrounding normal tissues

Clinical Applications and Implications

• Understanding cell cycle effects and radiosensitivity is crucial for optimizing radiotherapy treatment plans
• Fractionated radiotherapy is the standard approach for most solid tumors, balancing tumor control and normal tissue toxicity
• Altered fractionation schemes (hyperfractionation, hypofractionation) may be used in specific clinical scenarios
  • Hyperfractionation may be beneficial for rapidly proliferating tumors (head and neck cancers)
  • Hypofractionation may be used for slow-growing tumors (prostate cancer) or for palliative treatments
• Combining radiotherapy with chemotherapy or targeted agents can modulate radiosensitivity and improve treatment outcomes
• Predictive biomarkers of radiosensitivity (e.g., DNA repair gene mutations) may help personalize radiotherapy treatments
• Normal tissue toxicity remains a major limiting factor in radiotherapy, and strategies to minimize it are actively investigated

Future Directions and Research

• Developing more accurate predictive models of cell survival and normal tissue response
• Identifying novel biomarkers of radiosensitivity to guide treatment personalization
• Exploring the use of high linear energy transfer (LET) radiation (protons, carbon ions) to overcome radioresistance
• Investigating the role of the tumor microenvironment and immune system in modulating radiosensitivity
• Combining radiotherapy with immunotherapy to enhance anti-tumor immune responses
• Developing targeted radiosensitizers and radioprotectors to improve the therapeutic ratio
• Applying advanced imaging techniques (functional MRI, PET) to monitor treatment response and adapt radiotherapy plans
• Conducting clinical trials to validate new fractionation schemes and combination strategies