Physiology of Oncology

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Physiology of Oncology

• C. Bryce Bowling, MD
• Department of Obstetrics Gynecology
• University of Tennessee, Memphis

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Disclaimer

• Great attempts have been made to ensure I do not
  induce somnolence with this presentation
  however, I can make no guarantees, as the author
  fell asleep twice writing it.

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(No Transcript)
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CREOG Educational Objectives

• Describe the metabolic changes that occur in
  patients with a malignancy of the pelvic organs
  or breast
• Define the concept of therapeutic index
• Describe the changes in cellular physiology that
  result from injury caused by radiation and
  chemotherapy
• Describe the ability of vital organ systems to
  tolerate cancer therapy

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CREOG Objective One

• Describe the metabolic changes that occur in
  patients with a malignancy of the pelvic organs
  or breast.

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CREOG Objective OneMetabolic Changes of
Malignancy

• Abnormal Carbohydrate Metabolism
• Insulin resistance Glucose intolerance
• Increased glucose production
• Abnormal Protein Metabolism leading to extreme
  muscle wasting
• Decreased protein synthesis
• Increased protein catabolism
• Tumor derived products like PIF (proteolysis
  inducing factor) and endogenous factors like
  TNF-alpha cause increased protein catabolism
• Abnormal fat and carbohydrate metabolism leading
  to Wasting Syndrome (Cachexia)
• Stimulation of nausea / vomiting contributing to
  malabsorption
• Anemia leading to fatigue
• Increased resting energy expenditure also leading
  to fatigue

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CREOG Objective Two

• Define the concept of therapeutic index.

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CREOG Objective Two Therapeutic Index

• The ratio of the drug dose which produces a
  toxic effect (TD50) to the
  
  dose which causes the desired effects (ED50) is
  the therapeutic index.
• Simply put, TI toxic dose therapeutic
  dose or TD50 ED50.
• The Therapeutic Index indicates the
  selectivity of the drug and consequently its
  usability.
• It should be noted that a single drug can have
  many therapeutic indices, one for each of its
  undesirable effects relative to a desired drug
  action.

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CREOG Objective Two Therapeutic Index

• The higher the Therapeutic Index, the safer
  the drug.
• The important factor is to have a clear gap
  between the maximum dose required to produce the
  therapeutic effect and the minimum dose which
  will cause death or undesirable side effects.

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CREOG Objective Two Therapeutic Index

• For example, a study out of the Univ. of Arizona,
  Tucson showed Carboplatin-cyclophosphamide proved
  to have a significantly higher therapeutic index
  than cisplatin-cyclophosphamide in patients with
  stage III (suboptimal) and stage IV ovarian
  cancer, meaning it was safer.
• The study found the combination chemotherapeutic
  Carboplatin-cyclophosphamide to cause less nausea
  and emesis, less renal toxicity, less hearing
  loss and tinnitus, less neuromuscular toxicities,
  as well as less alopecia than compared to the
  cisplatin arm.
• 
  
  
  J Clin Oncol. 1992 May10(5)706-17.

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CREOG Objective Three

• Describe the changes in cellular physiology that
  result from injury caused by radiation and
  chemotherapy.

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CREOG Objective Three Chemotherapy

• The principle is to attain maximal therapeutic
  cytotoxic effects with causing extreme toxicity
  to normal tissues.
• How does Chemo injure the cell?

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CREOG Objective Three Cell Cycle
Many cancer drugs act by blocking one or more
stages of the cell cycle. In doing so, they
damage the dividing cancer cells and prevent
further production. Where do specific
chemotherapeutic drugs act in relationship to the
cell cycle?
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CREOG Objective Three Chemo Agents and Cell
Cycle Interruption

• Antimetabolites Antimetabolites interrupt the
  cell cycle by preventing DNA synthesis - the S
  phase.
• They interfere with the production of key
  molecules with the cell nucleic acids, RNA
  DNA.
• Examples of Antimetabolites
• Folate Antagonists such as MTX. MTX binds to and
  inhibits dihydrofolate reductase (DHFR), meaning
  Folate stays in its inactive form.
• Purine Antagonists such as 6-MP
  (6-Mercaptopurine). 6-MP inhibits purine
  nucleotide production thus halting DNA synthesis.
• Pyrimidine Antagonists such as 5-FU
  (5-fluorouracil). 5-FU inhibits the production of
  pyrimidine nucleotides, thus halting DNA
  synthesis.

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CREOG Objective Three Chemo Agents and Cell
Cycle Interruption

• Alkylating Agents (Cyclophosphamide, Cisplatin,
  Carboplatin)
• DNA alkylation produces a variety of defects that
  disrupt DNA replication and transcription by
  modifying DNA bases and their bonds.
• Defects caused include depurination,
  double-stranded and single-stranded breaks, as
  well as inter-strand cross-links which cell
  destruction and mutations.

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Mutant
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CREOG Objective Three Chemo Agents and Cell
Cycle Interruption

• Plant Alkaloids
• Vinca Alkaloids (derived from the periwinkle
  plant) - halt the mitosis phase of the cell cycle
  by binding to tubulin, thus preventing the
  assembly of microtubules responsible for
  chromosome migration. Example vincristine,
  vinblastine
• Paclitaxel or Taxol (isolated compound from the
  Pacific Yew tree) binds to microtubules and
  prevents their breakdown. Without the ability to
  breakdown, microtubules cannot pull chromosomes
  to opposite ends of the dividing cell.
• Etoposide (a derivative of the mandrake plant)
  inhibits topoisomerase II, an enzyme which
  normally unwinds DNA during replication to
  relieve tension on the unwinding strand. The DNA
  which has been nicked by topo II, is unable to
  unwind and eventually breaks under tension.
  
  

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CREOG Objective Three Chemo Agents and Cell
Cycle Interruption

• Antitumor Antibiotics all derivatives of
  species Streptomyces (Actinomycin D, bleomycin,
  mitomycin C, ect.).
• Act by either interfering with DNA, RNA and
  protein synthesis or by altering membranes
  surrounding the cells.

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CREOG Objective Three Radiation Therapy and the
Cell Injury Effect

• Cancer cells grow without appropriate external
  signals and do not exhibit contact inhibition
  therefore they grow much more rapidly than do
  normal cells.
• Radiation Therapy uses both x-rays and gamma rays
  to target cancerous growth. The high energy
  waves cause damage to DNA (break the hydrogen
  bonds linking DNA strands, disrupt cellular
  processes and division, and ultimately kill the
  cell).
• Simply put, damage caused by radiation (and by
  chemotherapy) is manifest much more quickly in
  tissues where the cells are dividing rapidly.

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CREOG Objective Three Radiation Drawbacks

• Tumors may grow again after ending radiotherapy
  To prevent regrowth, radiation is often coupled
  with surgery and/or chemotherapy.
• Large tumor masses often have oxygen-deficient
  cells in the center which do not divide as
  rapidly as those cells nearer to the surface. As
  a result, those cells are not as sensitive to
  radiation. For this reason, large tumors cannot
  be completely treated by radiation alone. Again,
  coupling radiation with Surgery and/or
  chemotherapy is often required.
• Also, because radiation is not specific to cancer
  cells, it can damage healthy cells as well. So,
  how do normal tissues tolerate radiation and/or
  chemotherapy?

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CREOG Objective Four

• Describe the ability of vital organ systems to
  tolerate cancer therapy.

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CREOG Objective FourVital Organ Systems Cancer
Treatment

• Again, damage caused by radiation and
  chemotherapy is manifest much more quickly in
  tissues where the cells are dividing rapidly.
• Vital organ systems are able to tolerate this
  because their cell cycle is more controlled and
  their rate of division is much slower.
• However, some organ systems have completely
  normal cells that do multiply quickly, and it is
  in these cells that the side effects of radiation
  and chemo are manifest.

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CREOG Objective FourVital Organ Systems Cancer
Treatment

• The fast-growing normal cells likely to be
  affected are
• Blood cells resulting in anemia, fatigue, and a
  higher susceptibility to infection
• Cells of the digestive tract, resulting in mouth
  ulcers, changes in the sense of taste, gum
  throat problems, diarrhea, constipation
• Cells of the reproductive system, resulting in
  permanent or temporary infertility, ED in men,
  and menopausal symptoms in women
• Hair follicles resulting in hair loss
• Nausea / vomiting is one of the most common
  complaints of treatment (it can also be induced
  by the following.)

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Excessive alcohol intake
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Summary

• Several metabolic changes occur in patients with
  a malignancy, including abnormal carbohydrate,
  fat, and protein metabolism. These changes lead
  to muscle wasting, cachexia, malabsorption and
  fatigue.
• The ratio of the drug dose which produces a toxic
  effect (TD50) to the dose which causes the
  desired effects (ED50) is the therapeutic index.
  (i.e. TI TD50 ED50)
• Chemotherapeutic Agents act by blocking one or
  more stages of the cell cycle. In doing so, they
  damage the dividing cancer cells and prevent
  further production.
• Radiation Therapy uses both x-rays and gamma rays
  to target cancerous growth. The high energy
  waves cause damage to DNA (break the hydrogen
  bonds linking DNA strands, disrupt cellular
  processes and division, and ultimately kill the
  cell).
• Coupling radiation with Surgery and/or
  chemotherapy is often required in larger tumors
  as radiation may not have an effect on
  slower-dividing, oxygen-deficient cells localized
  to the center of the tumor.
• Again, damage caused by radiation and
  chemotherapy is manifest much more quickly in
  tissues where the cells are dividing rapidly.
  Vital organ systems are able to tolerate this
  because their cell cycle is more controlled and
  their rate of division is much slower.
• Some organ systems have completely normal cells
  that do multiply quickly these cells are damaged
  by radiation and chemo and lead to undesired side
  effects.
• And finally, Dengle is a funny drunk.

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Questions?
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References

• Murphy, Lawrence, Lenhard American Cancer
  Society Textbook of Clinical Oncology , 2nd ed.,
  1995
• Lambrou, NC Trimble, E Chemotherapy Radiation
  Therapy , The Johns Hopkins Manual of Gynecology
  Obstetrics, 2 ed. 2002
• Orloff, GM, Moore, M, et al CancerQuest Emory
  University / Winship Cancer Institute
  http//www.cancerquest.org 2004
• US National Institute of Health, National Cancer
  Institute http//www.cancer.gov 2004