Radiobiology

☢️Radiobiology Unit 9 – Cell Cycle Effects and Radiosensitivity

Cell cycle effects and radiosensitivity are crucial concepts in radiobiology. They explain how cells respond to radiation at different stages of growth and division. Understanding these principles helps optimize cancer treatments and minimize damage to healthy tissues. Radiosensitivity varies throughout the cell cycle, with cells being most vulnerable during mitosis and G2 phase. This knowledge informs radiation therapy strategies, like fractionation, which exploits differences between normal and tumor cells to improve treatment outcomes.

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


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© 2024 Fiveable Inc. All rights reserved.
AP® and SAT® are trademarks registered by the College Board, which is not affiliated with, and does not endorse this website.