Study Guide: Radiation and Cancer Biology

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This exam tests your knowledge of the principles of cancer and radiation biology underlying the practice of radiation oncology. Included are questions on:

• basic cancer biology and the molecular biology of cancer
• the response to radiation at the subcellular and cellular levels
• the radiation responses of normal and malignant tissues
• radiation carcinogenesis
• hereditary effects as they relate to radiation protection

Categories for Cancer and Radiation Biology

Interaction of Radiation with Matter

• Definition of ionizing radiation and types
• Definition of LET and quality of radiation
• Generation of free radicals
• Direct and indirect action of radiation
• Role of oxygen

Molecular Mechanisms of DNA Damage

• Assays for DNA damage
• Neutral and alkaline elution, pulsed field electrophoresis, comet, plasmid-based assays
• Types of DNA lesions and numbers per cell/Gy
• Multiply damaged sites
• Single lethal hits and accumulated damage (inter- and intratrack)

Molecular Mechanisms of DNA Repair

• Types of repair
• Repair of base damage, single-strand and double-strand breaks
• Homologous recombination
• Nonhomologous end-joining

Chromosome and Chromatid Damage

• Assays
• Conventional and FISH
• Dose response relationships
• Use of peripheral blood lymphocytes in in vivo dosimetry
• Stable and unstable chromatid and chromosome aberrations 
• Human genetic diseases that affect DNA repair, fragility, and radiosensitivity

Mechanisms of Cell Death

• Apoptotic death
  • Developmental and stress induced
  • Morphological and biochemical features of apoptosis
  • Molecular pathways leading to apoptosis
  • Radiation-induced apoptosis in normal tissues and tumors
• Necrotic death
  • Morphological, pathological, and biochemical features of necrosis
• Mitotic death following irradiation
  • Catastrophic vs apoptotic death
  •  Cell division postradiation and time of clonogen death
• Radiation-induced senescence

Cell and Tissue Survival Assays

• In vitro clonogenic assays
  • Effects of dose, dose rate, cell type
• In vivo clonogenic assays
  • Bone marrow stem cell assays, jejunal crypt stem cell assay, skin clones, kidney tubules

Models of Cell Survival

• Random nature of cell killing and Poisson statistics
• Comparison of survival of viruses, bacteria, and eukaryotic cells after irradiation
• Single-hit, multitarget models of cell survival
• Two component models
• Linear quadratic model
• Calculations of cell survival with dose

Linear Energy Transfer

• RBE defined
• RBE as a function of LET
• Tissue type

Oxygen Effect

• Define OER
• Dose and dose per fraction effects
• OER vs LET
• Impact of O2 concentration
• Time scale of oxygen effect
• Mechanisms of oxygen effect

Repair at the Cellular Level

• Sublethal damage repair
• Potentially lethal damage repair
• Half-time of repair
• Dose rate effects and repair
• Dose fractionation effects

Solid Tumor Assay Systems

• Experimental models
• TD50 limiting dilution assay
• Tumor regrowth assay
• TCD50 tumor control assay
• Lung colony assay
• In vitro / in vivo assay
• Spheroid systems

Tumor Microenvironment

• Tumor vasculature
• Angiogenesis
• Hypoxia in tumors
  • Measurement of hypoxia
  • Transient and chronic hypoxia
• Reoxygenation following irradiation
• Relevance of hypoxia in radiation therapy
• Hypoxia as a factor in tumor progression
• Hypoxia-induced signal transduction
• Cellular composition of tumors

Cell and Tissue Kinetics

• Cell cycle
• Measurement of cell cycle parameters by 3H-thymidine
• Measurement by flow cytometry, DNA staining and BrdU
• Cell cycle synchronization techniques and uses
• Effect of cell cycle phase on radiosensitivity
• Cell cycle arrest and redistribution following irradiation
• Cell cycle checkpoints, cyclins, cyclin dependent kinase inhibitors
• Tissue kinetics
  • Growth fraction
  • Cell loss factor
  • Volume doubling times
  • Tpot
• Growth kinetics of clinical and experimental tumors

Molecular Signaling

• Receptor/ligand interactions
• Phosphorylation/dephosphorylation reactions
• Transcriptional activation
• Gene expression profiling and radiation-induced gene expression
• Radiation-induced signals
  • DNA damage response
  • Non-DNA damage response
• Cell survival and death pathways

Cancer

• Cancer as a genetic disease
• Oncogenes
• Tumor suppressor genes
• Telomeric changes in cancer
• Epigenetic changes in cancer (e.g., hypermethylation)
• Multistep nature of carcinogenesis
• Molecular profiling of cancer
• Signaling abnormalities in carcinogenesis
• Effects of signaling abnormalities on radiation responses
• Prognostic and therapeutic significance of tumor characteristics

Total Body Irradiation

• Prodromal radiation syndrome
• Cerebrovascular syndrome
• Gastrointestinal syndrome
• Hematopoietic syndrome
• Mean lethal dose and dose/time responses
• Immunological effects
• Assessment and treatment of radiation accidents
• Bone marrow transplantation

Clinically Relevant Normal Tissue Responses to Radiation

• Responses in skin, oral mucosa, oropharyngeal and esophageal mucous membranes, salivary glands, bone marrow, lymphoid tissue bone and cartilage, lung, kidney, testis, eye, central and peripheral nervous tissues

Mechanisms of Normal Tissue Radiation Responses

• Molecular and cellular responses in slowly and rapidly proliferating tissues
  • Cytokines and growth factors
  • Regeneration
  • Remembered dose
  • Functional subunits
• Mechanisms underlying clinical symptoms
  • Latency
  • Inflammatory changes
  • Cell killing
  • Radiation fibrosis
  • Volume effects
• Scoring systems for tissue injury
  • LENT and SOMA

Therapeutic Ratio

• Tumor control probability ( TCP) curves
  • Calculation of TCP
  • Factors affecting shape and slope of TCP curves
  • Influence of tumor repopulation/regeneration on TCP
• Normal tissue complication probability (NTCP) curves
  • Influence of normal tissue regeneration on responses
  • Response of subclinical disease
  • Causes of treatment failure
  • Factors determining tissue tolerance
  • Normal tissue volume effects
  • Dose-volume histogram analysis
• Effect of adjuvant or combined treatments on therapeutic rationals

Time, Dose, Fractionation

• The 4 R’s of fractionation
• The radiobiological rationalc behind dose fractionation
• The effect of tissue type on the response to dose fractionation
• Effect of tissue/tumor types on a/b ratios
• Quantitation of multifraction survival cures
• BED and isoeffect dose calculations

Brachytherapy

• Dose rate effects ( HDR and LDR)
• Choice of isotopes
• Interstitial and intracavitary use
• Radiolabeled antibodies

Radiobiological aspects of alternative dose delivery systems

• Protons, high LET sources, BNCT
• Stereotactic radiosurgery/radiotherapy, IMRT, IORT
• Dose distributions and dose heterogeneity

Chemotherapeutic agents and radiation therapy

• Classes of agents
• Mechanisms of action
• The oxygen effect for chemotherapy
• Multiple drug resistance
• Interactions of chemotherapeutic agents with radiation therapy
• Photodynamic therapy
• Gene therapy

Radiosensitizers, Bioreductive Drugs, Radioprotectors

• Tumor radiosensensitization
  • Halogenated pyrimidines, nitroimidazoles
• Hypoxic cell cytotoxins
  • Tirapazamine
• Normal tissue radioprotection
  • Mechanisms of action, sulfhydryl compounds, WR series, dose reduction factor ( DRF)
• Biological response modifiers

Hyperthermia

• Cellular response to heat
• Heat shock proteins
• Thermotolerance
• Response of tumors and normal tissues to heat
• Combination with radiation therapy

Radiation Carcinogenesis

• Initiation, promotion, progression
• Dose response for radiation-induced cancers
• Importance of age at exposure and time since exposure
• Malignancies in prenatally exposed children
• Second tumors in radiation therapy patients
• Effects of chemotherapy on incidence
• Risk estimates in humans
• Calculations based on risk estimates

Heritable Effects of Radiation

• Single gene mutation
• Chromosome aberrations
• Relative vs absolute mutation risk
• Doubling dose
• Heritable effects in humans
• Risk estimates for hereditable effects

Radiation Effects in the Developing Embryo

• Intrauterine death
• Congenital abnormalities and neonatal death
• Microcephaly, mental retardation
• Growth retardation
• Dose, dose rate, and stage in gestation
• Human experience of pregnant women exposed to therapeutic dose

Radiation Protection

• General philosophy
• Stochastic and deterministic effects
• Relative weighting factors
• Equivalent dose-tissue weighting factor
• Effective dose, committed dose
• Collective exposure dose
• Dose limits for occupational and public exposure
• ICRP and NCRP