Cellular Effects of Radiation

Cellular Effects of Radiation

Cellular Effects of Radiation

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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 double-strand break repair pathways

  • 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." Radiosensitivity across cell cycle phases

⭐ 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).

Cell survival curves: High vs Low LET

  • Modes of Radiation-Induced Cell Death:

    Death TypeFeatureRT Relevance
    Mitotic CatastropheMitotic failure post-irradiationMost common
    ApoptosisProgrammed; p53 dependent/independentCell-type dependent
    NecrosisUncontrolled; inflammationHigh dose effect
    SenescenceIrreversible G1 arrestContributes 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 TypeOER
      X-rays/γ-rays2.5-3.5
      Neutrons~1.6
      α-particles1
    • 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) OER and RBE Dose-Response Curves 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.

Practice Questions: Cellular Effects of Radiation

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Flashcards: Cellular Effects of Radiation

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Most radiosensitive tissue in our body is _____ and least radiosensitive is nervous tissue.

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Most radiosensitive tissue in our body is _____ and least radiosensitive is nervous tissue.

bone marrow

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