Lecture Introduction to Pharmacology by mikeholy


									Drugs Used in the treatment of Cancer

              Pharmacology 49.222
               Bill Diehl-Jones RN, PhD
    Faculty of Nursing and Department of Zoology
• Zen Review
    – What is cancer
•   General goals in cancer treatment
•   Targets of chemotherapy
•   Targets of radiotherapy
•   Breast cancer therapies
•   Prostate cancer therapies
   Characteristics of Cancer Cells
• The problem:
  –   Cancer cells divide rapidly (cell cycle is accelerated)
  –   They are “immortal”
  –   Cell-cell communication is altered
  –   They can disrupt normal, healthy tissues
The Cell Cycle
           Anticancer Drugs
• Some Solutions
  – Most cancer chemotherapies are designed to
    “hit” cell replication

• A problem:
  – This approach is non-specific
  – Most cancer chemotherapies kill cancer cells
    only slightly faster than normal cells
        Targets of Anticancer Drugs:
            Inhibitors of
           DNA Synthesis
    (Mercaptopurine, Methotrexate)

                                  Inhibitors of
                                  DNA Function
                              (Doxorubicin, Cisplatin)


      Inhibitors of
    DNA Replication                                      Protein
(Cytochalasin, Vincristine)
 The Goal of Cancer Treatments
• Curative
  – Total irradication of cancer cells possible?
  – The concept of “log kill”
     • If 109 cells present, and tmt kills 99.999%, then
       0.001% left
     • This is a 5-log kill
• Palliative
  – Alleviation of symptoms
  – Avoidance of life-threatening toxicity
        Cell Cycle-Dependant vs.
      Cell-Cycle Independent Drugs
• Some drugs kill cancer cells only at certain
  phases of the cell cycle:
  – Eg: Cytochalsin
  – Works only when a high ppn of cells are dividing
• Some drugs work throughout cell cycle:
  – Eg: Cisplatin
      Some General Chemotherapy
• Most drug therapies are combination
  – Eg: for ALL
     • “POMP”: Prednisone, Oncovin, Methotrexate, Purethinol
• Most chemotherapeutics have very low
  Therapeutic Indices
• Some treatments themselves may induce tumors
   Breast Cancer
 Hormonal Theory of Breast Cancer

• Reproductive risk factors include:
     • Early puberty, late menarche, short duration of
       breast feeding, nulliparity, delayed child birth
• Theory:
     • prolonged exposure to estrogen may initiate
       breast cancer
Exposure to Estrogen-like
Compounds Confers Risk
    of Breast Cancer
They may bind to same receptors,
    yield similar metabolites
Estrogen/Estrogen-like Molecules   Estrogen/Estrogen-Like Metabolites
 Induce Cell-Proliferation Genes          Form DNA Mutations


                                         Free Radicals
                                          OH•, O•
           DNA Adducts
      Why are they problematic?
• Adducts may disrupt key regulatory
  pathways in ductal cells
     • Eg: p53, ras
• Adducts can cause gene mutations:
                      C   G
                      A   T
     C   G
     A   T
                      C   G
     A   T
                      T   A
                      A   T
  Many Breast Cancer Therapies
Depend on Estrogen Receptor Status
  Blocking Estrogen Receptors
• Principle drug is TAMOXIFEN
  – Competes with estradiol for binding sites
  – Works in ER+ cancers
  – Often used in breast cancers which have
    metastasized to bone
     • May cause pain in affected site: a GOOD sign!
  – May cause eye damage
   Aromatase Inhibitors

A New Class of Breast Cancer Drugs
      NOT ER+ Dependant
     Estrogen from Two Sources May
          Initiate Breast Cancer:

            Androstenedione          Testosterone
               Estrone                Estradiol

                                         Endogenous Estrogen
                                           Due to aromatase
        Aromatase Inhibitors
• While Tamoxifen blocks a tumor’s abitlity
  to use estrogen, AI’s reduce the amount of
  estrogen in the body
• Three AI’s currently approved:
  – Anastrazole (Arimidex®)
  – Exestane (Aromasin®)
  – Letrozole (Femara®)
            The Bottom Line
• A major study of AI’s:
  – Breast cancer survivors taking letrozole after
    completing 5 years tamoxifen theraoy had
    significantly lower recurrence of breast cancers
    than women NOT on letrozole
             Prostate Cancer
• “It doesn’t matter who you are … if you are
  male and live long enough, you WILL get
  prostate cancer”
  – Bill Jones Sr.
 How is Prostate Cancer Detected?

          A combination is best
    Prostate Cancer Therapies
• Watch and wait
  – Generally a slow-growing cancer
• Surgery
  – Surgical excision, nerve-sparing (hopefully)
• Brachiitherapy
  – Implantation of radioactive pellets
         A Cancer Case Study
• HPI:
  – A 25 yo male athlete presents with severe cough, SOB;
    c/o a painful R. testicle
• O/E:
  – Non-encapsulated mass in testes; masses detected in
    abdomen, lungs and brain
• Dx:
  – Metastatic testicular cancer (choriocarcinoma, 40%
    embryonal, 1% teratoma
    Testicular Cancer Factoids
• Most common cancer in men 15 – 35
• 90% cure rate if detected early
• Method of detection:
  – Routine testicular palpation
• Surgical excision of testicle
• Surgery to remove 2 cancerous lesions on
• Chemotherapy:
  – 1 round of BEP (bleomycin, etoposide, platinol)
  – 3 rounds of VIP (Ifostamide, etoposide, platinol)
• Period of treatment:
  – October – December, 1996
Can you name the patient?
           Lance Armstrong
• 6-time Tour de France
  winner (AFTER
  getting cancer)
   Responsiveness to Chemotherapy
• These Cancers Respond:            • These may respond:
  –   Hodgkins lymphoma               – Breast, ovarian,
  –   ALL                               endometrial, myeloma,
  –   Choriocarcinoma                   large intestine, esophageal
  –   Wilm’s tumor
  –   Testicular, other germ line   • These do NOT respond:
                                      – Thyroid, Brain CA, liver,
                                        malignant melanoma,
                                        pancreatic, cervical

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