Mechanism

Radiation therapy primarily kills cancer cells by damaging their DNA. This happens in two main ways:

1. Direct Action: The radiation directly hits and ionizes the DNA molecule.
2. Indirect Action (More Common for X-rays/Gamma rays): Radiation interacts with water in the cell, creating highly reactive free radicals (especially hydroxyl radicals, OH⋅). These free radicals then diffuse and damage the DNA.

Key Points for USMLE:

• Main Target: DNA
• Lethal Lesion: Double-Strand Breaks (DSBs) are the most difficult for cells to repair and are the primary cause of cell death.
• Cell Death: The most common way irradiated cancer cells die is through mitotic catastrophe – they attempt to divide with damaged DNA and fail, leading to cell death. Apoptosis also occurs.
• Oxygen Effect: Radiation is more effective in the presence of oxygen because oxygen helps "fix" the free radical-induced damage, making it permanent. Hypoxic (low oxygen) tumors are more radioresistant.

Radiation injury

High doses of ionizing radiation (e.g., radiotherapy, nuclear accidents) cause DNA and cellular damage. Certain rapidly regenerating tissues (e.g., skin, gastrointestinal tissue, bone marrow) are more susceptible due to the depletion of immature parenchymal stem cells. Cancerous cells are more susceptible to radiation than healthy cells due to their high replication rates and dysfunctional DNA repair mechanisms.

• Mechanism
  • DNA double-strand breakage: Breakage of both strands is required; single-strand breaks can be repaired by polymerases.
  • Generation of reactive oxygen species: Unstable molecules formed by the ionization of water; oxygen free radicals can cause cellular and DNA damage.
• Easily affected cells:
  • GI: Intestinal crypt stem cells
  • Bone marrow: hematopoietic progenitors (pancytopenia)
  • Gonads: spermatogonia (infertility)
  • Skin: basal keratinocytes, hair follicle stem cells (desquamation, hair loss)

Acute radiation syndrome

Skin and mucosa (these are rapidly regenerating tissues)

• Erythema, desquamation, blisters, ulcers, necrosis
• Stomatitis, dysphagia
• Cataracts
• Hair loss
• Radiation dermatitis
  • Acute (<90 days after radiotherapy):
    • Apoptosis of basal keratinocytes and epidermal edema
    • Dose-dependent effects ranging from erythema to desquamation (ie, skin peeling), superficial ulceration, and/or blistering
    • Pigment changes and loss of skin appendages (eg, hair follicles, sebaceous glands)
  • Late (months to years after radiotherapy):
    • Fibrosis, characterized histologically by homogenization of dermal collagen, due to fibroblast activation by transforming growth factor-beta from damaged tissue and responding immune cells
    • Vascular damage, resulting in chronic hypoxia and ulceration
    • Abnormal, dilated microvasculature (ie, telangiectasias)

Respiratory

• Early radiation-induced lung injury: radiation pneumonitis
  • Usually develops within 3–12 weeks of radiation
  • Caused by an acute release of proinflammatory cytokines (e.g., IL-1, IL-6)
  • Common symptoms: dyspnea, dry cough, hemoptysis, and fever (patients may be asymptomatic)
  • Partial respiratory insufficiency is an early sign.

Chronic radiation injury

Results in fibrosis and/or cancer

Respiratory

• Late radiation-induced lung injury: radiation fibrosis
  • Usually develops after 6–12 months of radiation

Genitourinary

• Impaired fertility
  • Ovarian, vulvar and/or vaginal fibrosis, amenorrhea
  • Azoospermia
• Urethral and ureteral stenosis, lead to Urinary incontinence
• Bladder fibrosis
• Obstructive uropathy