Anticancer Drug Pharmacology

• This presentation covers the pharmacology of anticancer drugs in part 1.
• Dr. Asmaa El-rakhawy is a lecturer of Clinical Pharmacology at the Faculty of Medicine, Mansoura University.

Learning Outcomes

• Define cancer and its characteristics.
• Explain cell cycle kinetics and its relevance to drug mechanisms.
• Provide a classification of anticancer drugs.
• Discuss anticancer drug combinations and their benefits.
• Elucidate rescue therapy and its importance.
• Describe anticancer drug resistance.

Case Scenario

• A 32-year-old female underwent a segmental mastectomy for a 3 cm breast tumor.
• Lymph node sampling showed 2 involved nodes.
• The patient received postoperative treatment with antineoplastic drugs due to the established value of chemotherapy.
• Regimen included doxorubicin followed by cyclophosphamide/methotrexate/fluorouracil.

Cancer

• Neoplasm refers to the abnormal growth of tissue due to excessive cell division or a failure of cells to die when they should.
• A tumor is a mass or lump, representing a swollen lesion of this abnormal growth.
• Neoplasms or tumors can be benign or malignant, i.e., cancer.
• Benign tumors do not spread or invade nearby tissues or other body parts.
• Malignant tumors, spread and invade nearby tissues or other body parts.

Cancer Cells

• Cancer cells have four main characteristics that differentiate them from normal cells:
  • Uncontrolled proliferation
  • De-differentiation
  • Loss of function
  • Invasiveness and Metastasis

Cancer Treatment

• There are three main approaches to treating cancer:
  • Surgery (excision)
  • Radiotherapy (irradiation)
  • Chemotherapy (anticancer drugs)
• Chemotherapy can be the primary treatment or adjuvant to other lines of treatment.

Cell Cycle Specificity

• Cell cycle-specific agents (CCS) are effective only against replicating cells that are actively dividing.
• Cell cycle non-specific agents (CCNS) can kill cells in various and multiple phases of the cell cycle.

Classification of Anticancer Drugs

• Anticancer drugs classified by mechanism of action:
  • Cytotoxic Drugs:
    • Alkylating agents (CCNS): cyclophosphamide, cisplatin cause DNA alkylation leading to DNA strand breaks.
    • Antimetabolites (CCS in S phase): methotrexate, 6-mercaptopurine interfere with normal purine or pyrimidine nucleotide to inhibit DNA and RNA synthesis.
    • Vinca Alkaloids (plant) (CCS in M phase): vincristine, vinblastine block mitotic spindle formation.
    • Antibiotics (CCNS or CCS): doxorubicin, bleomycin, actinomycin disrupt DNA function and produce free radicals, which decrease DNA & RNA synthesis.
  • II. Hormones
  • III. Monoclonal antibodies

Adverse Effects

• Most anticancer drugs have a narrow therapeutic index, aiming to kill rapidly dividing cells.
• These drugs also affect normal cells undergoing rapid proliferation like:
  • Cells of the buccal mucosa
  • Gastrointestinal (GI) mucosa
  • Bone marrow
  • Hair
• General adverse effects:
  • GIT: nausea, vomiting, diarrhea & mal-absorption
  • Alopecia
  • Bone marrow depression: aplastic anemia, bleeding, opportunistic infections
  • Hyperuricemia
• Specific adverse effects:
  • Hepatic: methotrexate, 6-mercaptopurine
  • Renal: methotrexate, cyclophosphamide, cisplatin
  • Cardiac: doxorubicin
  • Pulmonary: bleomycin
  • Neuronal (nerve): vincristine & vinblastine

Combination Therapy

• Principles of combination chemotherapy:
  • Combine CCS and CCNS drugs.
  • Each drug should be active on its own.
  • Use agents with different mechanisms.
  • Use agents with non-overlapping toxic effects.
• Combination therapy advantages include synergism and minimized risk of toxicities and resistance.

Rescue Therapy

• The administration of a drug to counteract the effects of anticancer drugs on normal cells, thus decreasing side effects.
• Chemotherapeutic agent/Toxic effect and mechanism/Rescue therapy:
  • Methotrexate can cause bone marrow and GIT toxicities by antagonizing folic acid. Leucovorin is given as rescue therapy.
  • Cyclophosphamide can cause Hemorrhagic cystitis by releasing acrolein. MESNA is given as rescue therapy and traps acrolein.
  • Doxorubicin can cause cardiac toxicity by the generation of free radicals. Dexrazoxane is given as rescue therapy because it is a free radical "trapper".

Anticancer Drug Resistance

• Several causes of anticancer drug resistance:
  • Decreased activation of pro-drugs
  • Inactivation of anticancer drugs
  • Decreased drug accumulation
  • Increased DNA repair
  • Changes in target enzymes
• How to minimize drug resistance: intermittent therapy, short-term therapy, combinations of drugs.

Review Questions

• Cyclophosphamide is most likely responsible for acute hemorrhagic cystitis as a side effect.
• Plant alkaloids are cell cycle specific.