Radiobiology: Carcinogenesis

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Radiobiology Carcinogenesis

• 8 January 2009

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Clinical Carcinogenesis

• Second Primary Cancers (Therapy-related)
• 1/6 of all new diagnosed cancers in the US.
• Leading cause of death in cured Hodgkins patients
  
• Special concern in childhood cancers
• Frequently leukemias
• Mechanisms (multiple)
• Cancer is a genetic disease
• Multiple pathways to genome changes

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• Therapy-related cancers have been reported after
  structurally and mechanistically diverse
  treatments, in which the risk of developing these
  cancers is often dose dependent (such as for
  radiotherapy and alkylating agents).
• Radiotherapy and chemotherapy interact with other
  factors, such as hormonal status, cigarette
  smoking and genetic makeup, to modify the risk of
  developing a second cancer.
• Molecular, cellular and epidemiological evidence
  indicates the existence of discrete mechanisms of
  carcinogenesis.

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• Mechanism could involve either direct targeting
  of crucial transforming genes and relatively
  short latency of disease onset, or indirect
  targeting by the acquisition of a predisposing
  cellular phenotype (genomic instability) in which
  disease latency is longer.
• DNA double-strand breaks that are induced by
  chemotherapeutic topoisomerase inhibitors can
  lead to translocation of the mixed lineage
  leukaemia gene, as well as other crucial
  transforming genes.
• Chemotherapeutic methylating agents and
  thiopurines can promote the emergence of cells
  with dysfunctional DNA-mismatch repair and
  concomitant genomic instability.

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Dose-Response (Relative Risk)
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Latency related to agent
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Different Long-term effects Lymphomagenic
effects last a long time
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Note fix means to make permanent, not to repair
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1-2 Hit/Multiple Hit Models
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Mechanisms

• Genomic Instability Loss of heterozygosity is
  a consequence of genome instability leading to
  two copies of bad recessive gene.
• Mis-repaired Double Strand Breaks in DNA are
  thought to be critical lesion
• e.g., I125 decay is highly mutagenic relative to
  lethal effects
• Direct effects DNA lesions
• Indirect effects Cellular damage
• nuclear and cytoplasmic
• Indirect effects Bystander damage
• Cytokines, other factors

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Direct Effects

• Base damage relatively ineffective because of
  efficient repair.
• SSB efficiently repaired, too.
• DSB hard to repair correctly.
• Translocations lead to gene disruption and/or
  mis-regulation.

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Indirect effects Cellular Damage

• Transmissable genetic instability enhanced rate
  of mutation in progeny cells
• Effect is long-term but transient (persists for
  12-25 cell generations)
• Cytoplasmic irradiation (microbeam with alpha
  particles) not only a nuclear phenomenon
• Mechanism(s) is(are) still unclear

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Bystander Effects

• Increased mutation and transformation in
  undamaged cells in close proximity to damaged
  cells.
• Cell density effects
• Low-dose alpha irradiation
• Cell-cell communication via gap-junctions seem to
  be involved
• Secreted substances from damaged cells alter
  genetic stability of undamaged cells.

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Summary

• Aggressive post therapy surveillance and
  counseling
• Post-therapy changes in risk factors
• Considered selection of therapeutic agents to
  minimize risks
• Continued data accumulation for better predictive
  epidemiological models

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Two good reviews

• J.M. Allan and L.B. Travis, Mechanisms of
  Therapy-Related Carcinogenesis Nature
  Reviews/Cancer, 5943-955, 2005.
• J.B. Little, Radiation Carcinogenesis
  Carcinogenesis, 21397-404, 2000.