NUR 221 - Anti-cancer medications

Cancer

• Abnormal behavior of cancer cells results from alterations in their DNA

• Malignant transformation results from a combination of activating oncogenes (cancer-causing genes) and inactivating tumor suppressor genes (genes that prevent replication of cells that have become cancerous)

• Malignant transformation occurs in three major stages: initiation, promotion, and progression

Cancer features

• Lack control of mitosis and do not undergo apoptosis

• No normal organization or differentiation

• Abnormal cell membranes

Cancer treatment

• Surgery

• Radiation

• Gene therapy

• Anti-cancer medication (Chemotherapy)

Basics of anti-cancer medications

• Drug classes

  • Cytotoxic agents: used most often - Chemotherapy

  • Hormones and hormone antagonists

  • Targeted drugs

The cell cycle

• G0: resting

• G1: synthesis of components needed for DNA synthesis

• S: synthesis of DNA

• G2: synthesis of components needed for mitosis

• M: mitosis

Growth fraction

• The ratio of dividing cells to resting cells

• Tissues with large percentage of proliferating cells and few resting cells have a HIGH growth fraction

• Tissues with mostly resting cells have LOW growth fraction

Growth fraction and chemotherapy

• Chemotherapy drugs are more toxic to tissues with HIGH growth fraction

• Cytotoxic agents are more active against proliferating cells

  • Disrupt DNA synthesis

  • Disrupt mitosis

Obstacles to successful chemotherapy

• Cancer response to chemotherapy

  • Breast, lung, prostate, colon cancers have low growth fraction and don’t respond to chemotherapy as well as acute lymphocytic leukemia, Hodgkin’s disease (high growth fraction)

• Toxicity to normal cells - dose limiting

  • Lack selective toxicity to cancer cells

• Cure requires elimination of every malignant cell

  • One cell can proliferate and cause relapse

• Kinetics of drug induced cell kill

  • At any given dose - drug will kill constant percentage of malignant cells regardless of how many cells are actually present

Anticancer medications and host defenses

• Anticancer medications receive little help from host defenses

  • Cancers cells have same surface antigens as normal cells

  • Anticancer drugs are immunosuppressants

  • Immune system might be compromised of cancer itself

Absence of early detection

• Before 1 g tumor = higher growth fraction, shorter doubling time

  • One billion cancer cells (1 g) = smallest detectable tumor

• After 1 g tumor = lower growth fraction, longer doubling time

  • One trillion cancer cells (1 kg) = lethal

Obstacles to successful chemotherapy - drug resistance

• Reduced drug uptake

• Increased drug efflux

• Reduced drug activation

• Reduced target molecule sensitivity

• Increased repair of drug induced damage to DNA

Obstacles to successful chemotherapy - ongoing mutation

• Cells not identical

• Subpopulation of dissimilar cells

Obstacles to successful chemotherapy - limited drug access

Location and blood supply

Acheiving maximum benefits from chemotherapy - intermittent chemotherapy

Normal cells must repopulate faster for intermittent chemo to work

Acheiving maximum benefits from chemotherapy - combo chemotherapy

• Combination of drugs

  • Suppression of drug resistance

    • Low probability of developing 2 or more mutations

  • Increased cancer cell kill

    • Different mechanism of action

  • Reduced injury to normal cells

    • Avoid overlapping toxicities

Guidelines for drug selection

• Should be effective by itself

• Each drug should have different mechanism of action

• Drugs should have minimally overlapping toxicities

• Dosing schedules

  • Combination should have different MOAs

  • Schedules maximize beneficial effects of medications

Delivery of chemotherapy

• Central line or port

• Very damaging to peripheral vessels - increasing pain and side effects

• Regional delivery routes

  • Avoid systemic effects

  • Ex. directly into bladder for treatment of bladder cancer

Side effects of chemotherapy - bone marrow suppression

• Neutropenia

• Thrombocytopenia

• Anemia

Neutropenia

• Decreased neutrophils

• Normal 2500-7000 cells/mm³

• Absolute neutrophil count < 500/mm³

Thrombocytopenia

• Decreased platelets'

• Normal 150,000-450,000 per mcL

Anemia

Reduction in red blood cells

Side effects of chemotherapy - stomatitis

• Inflammation of oral mucosa

• Develops within a few days

• Can persist for 2 weeks post-treatment

• Impacts

  • Ulceration

  • Pain with eating, swallowing, speaking

  • Risk for oral candida

Side effects of chemotherapy - nausea and vomiting

• Caused by direct stimulation of the chemoreceptor trigger zone

  • Immediate and dramatic

  • May persist for hours/days

  • Can cause dehydration and malnutrition

• Pre-medicate prior to treatment

  • Ondansetron (Zofran) 8mg PO twice on day 1

    • MOA: selectively antagonizes serotonin 5-HT3 receptors

    • Side effects: HA, constipation, diarrhea, dizziness, QT prolongation

Side effects of chemotherapy - alopecia

• Reversible alopecia results from injury to hair follicles

• Occurs with most cytotoxic medications

• Begins 7-10 days post-treatment

• Regeneration begins 1-2 months after last course of treatment

• Cooling scalp during chemo in attempt to reduce hair loss

  • Vasoconstriction and reduces drug delivery to hair follicles

  • Is uncomfortable, causes headache

Alkylating agents

• Cytotoxic medications

• Cell cycle phase nonspecific b/c reactions can take place at anytime

• Cell kill results from alkylation of DNA

• Example: Cyclophosphamide

Platinum compounds

• Cytotoxic medications

• Cell cycle phase nonspecific, cross links DNA

• Example: Cisplatin

Antimetabolites

• Cytotoxic medications

• Folic acid analogs

  • Methotrexate: S-phase specific - disrupts DNA synthesis

• Pyrimidine analogs

  • Fluorouracil: S-phase specific - inhibits DNA and RNA synthesis (kills dividing cells only)

Mitotic inhibitors

• Cytotoxic medications

• Act during M-phase to prevent cell division

• Vincristine

Vincristine

Inhibits microtubule formation, stopping mitosis in metaphase

Decision to treat with chemotherapy

• Basic benefits

  • Cure, prolongation of life, palliative treatment

• General health of patient

• Type of cancer and responsiveness to chemotherapy

• Karnofsky Performance Scale

  • Less than 40 indicates patient unlikely to tolerate chemotherapy

Hormonal agents

• Used primarily for breast cancer and prostate cancer

• Mimic or block the actions of endogenous hormones

Tamoxifen

• Used for anti-estrogen breast cancer

• Block estrogen receptors

• Used for established breast cancer disease and for reducing occurrence in high-risk patients

Tamoxifen adverse effects

• Hot flashes

• Fluid retention

• Vaginal discharge

• Nausea and vomiting

• Menstrual irregularities

• Endometrial cancer

• Teratogenic

Leuoprolide

• Leupron

• Hormonal treatment

• Inhibits gonadotropin release, suppressing ovarian and testicular steroidogenesis

Leuoprolide adverse effects

• Generally well tolerated

• Hot flashes

• Testosterone loss may aggravate bone pain

Targeted drugs

• Designed to bind with specific targets to suppressing tumor growth

  • Antibodies that bind with specific antigens on tumor cells

  • Small molecules that inhibit intracellular enzymes

  • Mark cancer cells for immune attack