Cellular Effects of Radiation

Radiation's Cellular Hit - Target Practice

• Direct Action: Radiation directly ionizes key cellular targets (DNA, RNA, proteins). Predominant with high-LET radiation (α, neutrons). Causes base damage, SSBs, DSBs.
• Indirect Action: Radiation interacts with $H_2O$, creating free radicals.
  • $H_2O \xrightarrow{radiation} H_2O^{\cdot+} + e^- \rightarrow H_3O^+ + OH^\cdot$
  • $OH^\cdot$ (hydroxyl radical) is most damaging.

  ⭐ Indirect action, mediated by free radicals like the hydroxyl radical, accounts for about 2/3 of DNA damage from low-LET radiation (X-rays, γ-rays).

• Target Theory: Cell death if critical targets (DNA) hit. $D_0$: dose for 37% survival.

DNA's Radiation Wounds - Code Red & Fix

• DNA: Principal target for radiation cell death & heritable effects.
• Damage Mechanisms:
  • Direct Action: Radiation directly ionizes DNA.
  • Indirect Action: Via H₂O radiolysis (OH• radicals); dominant for X/γ-rays.
• Lesion Types:
  • Base Damage (BD): e.g., 8-oxoG.
  • Single-Strand Breaks (SSBs): Usually readily repaired.
  • Double-Strand Breaks (DSBs): Most lethal; cause mutations/aberrations.
  • DNA-Protein Crosslinks (DPCs)
  • Clustered Lesions: Multiple damages nearby.
• Repair Pathways:
  • Base Excision Repair (BER): For non-bulky base damage.
  • Nucleotide Excision Repair (NER): For bulky adducts.
  • Single-Strand Break Repair (SSBR): Involves PARP.
  • DSB Repair:
    • NHEJ (Non-Homologous End Joining): Fast, error-prone; G1, S, G2 phases.
    • HRR (Homologous Recombination): Accurate, uses sister chromatid; late S/G2.

⭐ Double-Strand Breaks (DSBs) are the most critical lesions for radiation-induced cell killing, chromosomal aberrations, and mutations.

Cell Cycle Sensitivity - Phase Fright

• Cell vulnerability to radiation fluctuates through its cycle.
• Most Radiosensitive Phases:
  • M phase (Mitosis): Chromosomes condensed, limited repair time.
  • G2 phase: Pre-mitotic checkpoint, damage assessed before division.
• Most Radioresistant Phase:
  • Late S phase: DNA homologous recombination repair most active.
• Intermediate Sensitivity:
  • G1 phase, Early S phase.
• 📌 Mnemonic: "Mighty G2 Guards, Late S Survives."

⭐ Cells are generally most radiosensitive in M and G2 phases, and most radioresistant during the late S phase due to efficient DNA repair mechanisms.

Cell Death & Survival - Counting Casualties

• Linear-Quadratic (LQ) Model: Describes cell kill: $S = e^{-(\alpha D + \beta D^2)}$

  • $\alpha$: linear component (non-repairable damage).
  • $\beta$: quadratic component (repairable damage interaction).
  • $\alpha/\beta$ ratio: Dose where linear kill ($\alpha D$) equals quadratic kill ($\beta D^2$).

• Cell Survival Curve: Plots surviving fraction vs. dose.

  • $D_0$: Mean lethal dose (dose to reduce survival to 37% on exponential part). $\uparrow D_0 = \uparrow$Radioresistance.
  • $D_q$: Quasi-threshold dose (measures shoulder, SLDR capacity).
  • $n$: Extrapolation number (also measures shoulder).

• Modes of Radiation-Induced Cell Death:

  Death Type	Feature	RT Relevance
  Mitotic Catastrophe	Mitotic failure post-irradiation	Most common
  Apoptosis	Programmed; p53 dependent/independent	Cell-type dependent
  Necrosis	Uncontrolled; inflammation	High dose effect
  Senescence	Irreversible G1 arrest	Contributes to effect

⭐ The alpha/beta ratio is key in radiotherapy. Low (2-4 Gy) for late-responding tissues (more fractionation sensitive); high (8-10 Gy) for early-responding tissues & most tumors (less fractionation sensitive).

Response Modifiers - Dialing Damage

• Oxygen Effect: ↑ radiosensitivity.
  • OER ($OER = \frac{Dose\ in\ hypoxia}{Dose\ in\ aerated\ conditions}$):

    Radiation Type	OER
    X-rays/γ-rays	2.5-3.5
    Neutrons	~1.6
    α-particles	1

  • Mechanism: Fixes free-radical DNA damage.

⭐ Oxygen is the most potent radiosensitizer; its effect is maximal at $pO_2$ levels around 20-30 mmHg and negligible for high-LET radiations.

• Radiosensitizers:
  • Halogenated pyrimidines (5-BUdR, 5-IUdR)
  • Hypoxic sensitizers (Misonidazole)
• Radioprotectors:
  • Sulfhydryl compounds (Amifostine/WR-2721) - free radical scavengers. DRF ~2.7.
• Cell Cycle:
  • Most sensitive: M, G2 phases.
  • Most resistant: Late S phase. (📌 Mnemonic: Mighty God 2 kill, Strong to survive) vs pO2 OR Graph of RBE vs LET)

High‑Yield Points - ⚡ Biggest Takeaways

• DNA is the principal target for radiation-induced cell death.
• Double-Strand Breaks (DSBs) are the most lethal DNA damage.
• Cells are most radiosensitive in M and G2 phases; most resistant in late S phase.
• Oxygen significantly enhances radiosensitivity (OER).
• Law of Bergonie & Tribondeau: Actively dividing, undifferentiated cells are more sensitive.
• The 4 R's of Radiobiology: Repair, Repopulation, Redistribution, and Reoxygenation.
• Apoptosis & mitotic catastrophe: key mechanisms of radiation-induced cell death.