Chapter 12 Notes

• Cancer Treatments


  • Surgery
  • Radiation
  • Chemotherapy
  • Molecularly Targeted Therapies
  • Emerging treatments
  • Angiogenesis
  • Immunotherapy
  • Epigenetic targeting
• Surgery


  • The oldest approach of treating cancer
  • 1890 the first mastectomy - complete removal of the breast in women with breast cancer
• Types of surgery for cancer treatment

  • Scalpel surgery
  • Laser surgery (cervix, larynx, liver, skin, rectum)
  • Electrosurgery (skin and mouth)
  • Cryosurgery (prostate cancers, dysplastic cervix)
• Laser surgery


  Highly focused beam of laser light
• Electrosurgery


  High frequency electrical current
• Cryosurgery


  Liquid nitrogen spray to freeze or kill cancer cells
• Radiation Therapy


  • Surgery is not always sufficient or practical
  • High-energy X-rays to kill cancer cell
• Brain tumours - surgery could cause brain damage
• Leukemias - cancer in bloodstream
• Radiation Therapy


  • Radiation kill cancer cells in two ways: p53 activation and activation of cell death by apoptosis (p53 wild type tumours)
  • Chromosomal damage severe enough to prevent cells from progressing through mitosis and the cells die while trying to divide
  • Cells that divide more frequently (cancer cells) are more susceptible to mitotic death than cells that divide less frequently (normal cells)
• Goals of Cancer Chemotherapy


  • Cure
  • Prolong survival
  • Palliation
• Chemotherapy


  Use of drugs that either kill cancer cells or interfere with the ability of cancer cells to proliferate
• Use of Chemotherapeutic Agents

  • Combination Therapy
  • Adjuvant Therapy (administered after primary therapy)
  • Neo Adjuvant Therapy (given before surgery to reduce tumour size)
• Chemotherapy Drugs


  • Antimetabolites
  • Alkylating Agents
  • Antibiotics
  • Hormone Therapy
• Antimetabolites


  Molecules that resemble substances involved in normal cellular metabolism. Enzymes bind to antimetabolites in place of normal molecules, disrupting essential metabolic pathways and poisoning the cell. Most of the antimetabolites used in cancer therapy disrupt pathways required for normal DNA synthesis and repair.
• Alkylating agents


  Induce covalent modifications of DNA, creating adducts that cannot be removed by cells' repair machinery.
• Alkylating agents


  • Nitrogen mustard (mechlorethamine) - Hodgkin's lymphoma
  • Platinating agents
  • DNA-crosslinking agents containing platinum
  • Cisplatin - cures 90-95% of testicular cancer; also used for treatment of ovary, breast, pancreatic, lung cancers
• Antibiotics


  • Anticancer substances produced by bacteria
  • Many antibiotics for cancer treatments are produced in Streptomyces strain of bacteria
  • Target DNA molecule by different mechanisms
• Antibiotic agents


  • Doxorubicin - Insert themselves into DNA and inhibit the action of topoisomerase, an enzyme that normally breaks and rejoins DNA strands during DNA replication to prevent excessive twisting of the double helix
  • Bleomycin - Triggers DNA strand breaks
• Hormone therapy


  Treatment for cancers that arise in hormone-dependent tissues (e.g. breast, prostate, ovary)
• Prostate cancer hormone treatment


  • Prostate cancer patients - androgen (testosterone dependence); testicle removal; increased survival (Charles Huggins)
  • Gonadotropins control androgen production
  • Leuprolide is an analog of the gonadotropin-releasing hormone
• Breast cancer hormone treatment

  • Breast cancers dependent on estrogen for proliferation (ER+)
  • Drugs that block estrogen action - tamoxifen
  • Tamoxifen is administered to breast cancer patients whose tumours require estrogen, it binds to estrogen receptors in place of estrogen and prevents the receptors from being activated.
• Chemotherapy toxicity


  • With the exception of hormones, most chemotherapeutic drugs are toxic - detrimental to normal dividing cells as well as to cancer cells.
  • Commonly affected normal cells: cells lining hair follicles (hair loss), gastrointestinal tract and the bone marrow (nausea, vomiting, defective blood clotting, immune deficiency)
• Chemotherapy drug resistance


  • Drug resistance develops for almost all the drugs and cancer types under treatment
  • Mechanisms of resistance: Mutation of amplification of proteins targeted by therapy, Expression of drug-pumping proteins, multidrug resistance transport proteins, Mutations in genes that disable apoptosis, Cancer Stem Cells
• Molecularly Targeted Anticancer Treatment


  Based on compounds that interfere with cell targets directly connected with pathogenic events. Such therapies are expected to target specifically tumour cells, thus allowing for strong anticancer effects and minimal toxicities.
• Possible targets


  • The interaction between the ligand and its specific receptor - blocking the reaction
  • The cell cycle checkpoint - re-imposing checkpoint arrest
  • The apoptosis - proapoptotic molecules
  • Neoangiogeneis - angiogenesis inhibitors
  • The immune compartment of the host - modulating the immune response
• "Oncogene addiction" Theory


  Tumour cells, despite their plethora of genetic alterations, can exhibit dependence on a single oncogenic pathway or protein for its sustained proliferation
• Drugs


  Distinct and complementary modes of cell killing
• Mechanisms of drug action are not completely understood despite the success
• Caveat: systemic toxicity and multi-drug resistance
• Stem cell transplantation


  1. High-dose chemotherapy

  2. Treatment with stem cell transplantation to replenish person's hematopoietic stem cells
• Caveat: graft-versus-host disease
• Molecularly Targeted Anticancer Treatment


  Based on compounds that interfere with cell targets directly connected with pathogenic events
• Such therapies are expected to target specifically tumour cells, thus allowing for strong anticancer effects and minimal toxicities
• Possible targets


  • The interaction between the ligand and its specific receptor - blocking the reaction
  • The cell cycle checkpoint - re-imposing checkpoint arrest
  • The apoptosis - proapoptotic molecules
  • Neoangiogeneis - angiogenesis inhibitors
  • The immune compartment of the host - modulating the immune response
• "Oncogene addiction" Theory


  Tumour cells, despite their plethora of genetic alterations, can exhibit dependence on a single oncogenic pathway or protein for its sustained proliferation and/or survival
• Switching off crucial oncogenes/pathways should have devastating effects on cancer cells while sparing normal cells
• "Oncogene addiction" sets the stage for Molecularly Targeted Cancer Therapy
• Small molecule inhibitors


  Low-molecular-weight organic compounds that target a molecule that must be druggable: contain a well-defined pocket that can specifically bind small molecule inhibitors
• Monoclonal antibodies


  Molecularly Targeted Anticancer Treatment