☢️Radiobiology Unit 4 – Cellular Radiobiology: Biomolecular Effects

Key Concepts and Terminology

• Radiobiology studies the effects of ionizing radiation on living organisms at the molecular, cellular, tissue, and systemic levels
• Ionizing radiation can directly or indirectly damage biomolecules, leading to cellular dysfunction or death
• Linear energy transfer (LET) measures the amount of energy deposited per unit length of the radiation track and influences the biological effectiveness of radiation
• Relative biological effectiveness (RBE) compares the biological effects of different types of radiation to a reference radiation (usually X-rays or gamma rays)
• Radiosensitivity refers to the susceptibility of cells, tissues, or organisms to the harmful effects of ionizing radiation
• The law of Bergonié and Tribondeau states that cells are more radiosensitive if they have a high mitotic rate, a long mitotic future, and are undifferentiated
• Oxygen enhancement ratio (OER) describes the increased sensitivity of cells to radiation in the presence of oxygen due to the formation of reactive oxygen species (ROS)
• Dose fractionation involves delivering the total radiation dose in smaller, multiple fractions to allow normal tissue repair and reduce side effects

Cellular Structure and Radiation Targets

• The main cellular targets of ionizing radiation are DNA, proteins, and lipids
• DNA is the most critical target due to its role in storing genetic information and directing cellular functions
• Radiation can cause single-strand breaks (SSBs), double-strand breaks (DSBs), base damage, and DNA-protein crosslinks
• Proteins can undergo oxidation, denaturation, and crosslinking when exposed to radiation, affecting their structure and function
• Lipids in cell membranes are susceptible to lipid peroxidation, leading to membrane damage and altered permeability
• Mitochondria are also sensitive to radiation due to their role in energy production and the generation of reactive oxygen species (ROS)
• The nucleus is a major target of radiation damage, as it contains the cell's genetic material
• Chromatin structure and compaction can influence the cell's radiosensitivity, with more condensed chromatin being less susceptible to radiation damage

Types of Radiation and Their Interactions

• Ionizing radiation can be classified as electromagnetic (X-rays and gamma rays) or particulate (alpha particles, beta particles, neutrons, and heavy ions)
• Electromagnetic radiation interacts with matter through the photoelectric effect, Compton scattering, and pair production, depending on the photon energy
• Alpha particles have high LET and short range, causing dense ionization tracks and significant biological damage
• Beta particles have lower LET and longer range compared to alpha particles, resulting in more scattered ionization events
• Neutrons can cause direct and indirect ionization, with high LET and significant biological effectiveness
• Heavy ions (e.g., carbon ions) have very high LET and are used in advanced radiotherapy techniques due to their precise dose deposition and increased biological effectiveness
• The type and energy of radiation influence the pattern and extent of cellular damage
• Indirect effects of radiation occur when radiation interacts with water molecules, generating free radicals (e.g., hydroxyl radicals) that can damage biomolecules

DNA Damage and Repair Mechanisms

• Ionizing radiation can induce various types of DNA damage, including SSBs, DSBs, base damage, and DNA-protein crosslinks
• DSBs are considered the most critical type of DNA damage, as they can lead to chromosomal aberrations and cell death if left unrepaired
• Cells have evolved several DNA repair mechanisms to maintain genomic integrity:
  • Base excision repair (BER) corrects small base lesions and SSBs
  • Nucleotide excision repair (NER) removes bulky DNA adducts and UV-induced damage
  • Homologous recombination (HR) and non-homologous end joining (NHEJ) repair DSBs
• The choice of repair pathway depends on the type of damage, cell cycle stage, and availability of repair proteins
• Misrepair or incomplete repair of DNA damage can result in mutations, chromosomal aberrations, and genomic instability
• Deficiencies in DNA repair genes (e.g., BRCA1, BRCA2, ATM) can increase radiosensitivity and cancer risk
• The efficiency of DNA repair mechanisms influences the cell's ability to recover from radiation-induced damage
• Modulating DNA repair pathways is an active area of research for enhancing radiotherapy outcomes

Cellular Response to Radiation

• Cells respond to radiation-induced damage through various pathways, including cell cycle arrest, DNA repair, apoptosis, and senescence
• Cell cycle checkpoints (G1, S, G2/M) are activated in response to DNA damage to halt cell cycle progression and allow time for repair
• p53, a tumor suppressor protein, plays a crucial role in regulating cell cycle arrest, DNA repair, and apoptosis in response to radiation
• Apoptosis, or programmed cell death, is a common response to irreparable DNA damage and helps eliminate potentially harmful cells
• Senescence is a state of permanent cell cycle arrest that can be induced by radiation, preventing further cell division
• Radiation can also trigger inflammatory responses and the release of cytokines, which can affect the surrounding tissue microenvironment
• Bystander effect refers to the phenomenon where irradiated cells communicate damage signals to non-irradiated neighboring cells, inducing similar responses
• Adaptive responses, such as increased antioxidant defense and DNA repair capacity, can occur in cells exposed to low doses of radiation
• The cellular response to radiation is influenced by factors such as cell type, dose, dose rate, and the presence of oxygen and other modifying agents

Dose-Response Relationships

• Dose-response relationships describe the connection between the absorbed dose of radiation and the biological effect observed
• Linear no-threshold (LNT) model assumes that the risk of radiation-induced effects increases linearly with dose, without a threshold
• Linear-quadratic (LQ) model is widely used in radiotherapy and assumes that the biological effect is proportional to the square of the dose at high doses
• The $\alpha/\beta$ ratio in the LQ model represents the dose at which the linear and quadratic components of cell killing are equal
• Tissues with high $\alpha/\beta$ ratios (e.g., tumors, early-responding tissues) are more sensitive to changes in fraction size, while those with low $\alpha/\beta$ ratios (e.g., late-responding tissues) are more sensitive to changes in total dose
• Hyper-radiosensitivity (HRS) and increased radioresistance (IRR) are observed in some cell lines at very low doses, deviating from the LNT model
• Hormesis is a controversial concept suggesting that low doses of radiation may have beneficial effects, such as stimulating repair mechanisms and adaptive responses
• The shape of the dose-response curve can vary depending on the endpoint measured (e.g., cell survival, mutation frequency, tumor control)
• Understanding dose-response relationships is crucial for optimizing radiation therapy protocols and assessing radiation risks

Radiobiological Models and Theories

• The target theory assumes that radiation must hit a specific target (e.g., DNA) to produce a biological effect and that the probability of a hit follows a Poisson distribution
• The linear-quadratic (LQ) model is a mathematical model that describes cell survival as a function of radiation dose, accounting for both single-hit and double-hit events
• The biologically effective dose (BED) is a concept that allows for the comparison of different fractionation schemes by considering the total dose and the $\alpha/\beta$ ratio
• The Lea-Catcheside dose protraction factor accounts for the impact of dose rate on cell survival, as repair processes can occur during prolonged exposures
• The lethal-potentially lethal (LPL) model distinguishes between lethal lesions that are irreparable and potentially lethal lesions that can be repaired under appropriate conditions
• The dual radiation action (DRA) theory proposes that the biological effect of radiation is proportional to the square of the energy deposition events within a sensitive site
• The repair-misrepair (RMR) model considers the competition between correct repair and misrepair of DNA damage in determining the ultimate biological outcome
• The tumor control probability (TCP) and normal tissue complication probability (NTCP) models are used to predict the likelihood of tumor control and normal tissue toxicity in radiotherapy
• Radiobiological models and theories provide a framework for understanding and predicting the complex biological responses to radiation exposure

Clinical and Practical Applications

• Radiobiology principles are applied in radiation oncology to optimize cancer treatment plans, balancing tumor control and normal tissue sparing
• Fractionation schemes (conventional, hypofractionation, hyperfractionation) are designed based on the $\alpha/\beta$ ratios of tumors and normal tissues
• Dose-volume histograms (DVHs) are used to evaluate the dose distribution in target volumes and organs at risk, aiding in treatment plan optimization
• Radiosensitizers (e.g., oxygen, chemotherapeutic agents) are used to enhance the effects of radiation on tumors, while radioprotectors (e.g., amifostine) are used to reduce normal tissue toxicity
• Brachytherapy, a form of internal radiotherapy, relies on the inverse square law to deliver high doses to tumors while sparing surrounding normal tissues
• Particle therapy (e.g., proton, carbon ion) exploits the physical properties of charged particles to deliver conformal dose distributions and reduce normal tissue exposure
• Radiobiological considerations are important in space radiation protection, as astronauts are exposed to high-energy cosmic rays and solar particle events
• Radiation biodosimetry techniques, such as chromosome aberration analysis and gene expression profiling, are used to estimate the absorbed dose in exposed individuals
• Radiobiology research aims to identify novel targets and strategies for enhancing radiation response, such as targeting DNA repair pathways, immune modulation, and combination therapies