Pharmacology: Cancer and Chemotherapy

Cancer (Neoplastic Disease)

• Cancer is a group of diseases characterized by abnormal cell growth and a shift in control mechanisms for growth and differentiation.
• Cancer cells infiltrate into organs and interfere with normal functioning.
• There is no single cure for cancer.

Cancer Statistics

• Second leading cause of death in the US (500,000 deaths per year).
• Common cancer types in males: lung, prostate, colon and rectum.
• Common cancer types in females: lung, breast, colon and rectum, and uterus.

Types of Cancers

• Hematologic Malignancies: tumors of blood-forming organs and cells.
  • Leukemias: proliferation of immature progenitors that circulate in blood.
    • Acute lymphocytic leukemia (ALL): proliferation of immature lymphoblasts in bone marrow.
    • Chronic lymphocytic leukemia (CLL): proliferation of immature B cells.
    • Acute myelocytic leukemia (AML): proliferation of immature myeloid cells in bone marrow.
    • Chronic myelocytic leukemia (CML): proliferation of myeloid cells; characterized by the Philadelphia chromosome.
  • Lymphomas: tumors of the lymph system.
    • Hodgkin's Disease: cancer of lymph nodes.
    • Non-Hodgkin's lymphoma: cancer of lymphocytes.

Solid Tumors

• Can occur in any organ or tissue; malignant (metastatic and invasive).
• Carcinomas: arise from epithelial cells; malignant by definition.
  • Examples: squamous cell carcinoma (arises from basal cells of skin); glandular epithelial cells of breast.
• Sarcomas: cancer of connective or supportive tissue (bone, cartilage, fat, muscle, blood vessels) and soft tissue.
  • Examples: osteogenic sarcoma (arises from osteoblasts, chondroblasts, fibroblasts).

Cancer Chemotherapy

• Goal: to be discussed.
• Selective Toxicity: to be discussed.
• Immune System: to be discussed.
• Other aspects of cancer chemotherapy: to be discussed.### Hodgkin's Disease
• Examples of Hodgkin's disease treatment: vincristine, methotrexate, 6-mercaptopurine, and prednisone (acute childhood lymphoblastic leukemia)

Adjuvant Therapy

• Use of drugs in addition to surgery and radiation therapy to remove localized tumors and any remaining tumor cells
• Cytotoxic chemotherapy (CCT) is used to eliminate remaining tumor cells and prevent metastasis

Drug Toxicity

• CCT agents have a therapeutic index of 1, meaning the therapeutic dose is similar to the toxic dose
• Cytotoxic agents kill all rapidly growing cells, including:
  • Bone marrow cells, leading to leukopenia, thrombocytopenia, and anemia
  • GI tract cells, leading to vomiting, diarrhea, and ulceration
  • Hair follicles, leading to alopecia
  • Tissues undergoing repair, leading to impaired wound healing
  • Tumor cells, leading to hyperuricemia and kidney damage

Classes of Cancer Chemotherapeutic Agents

• Inhibitors of DNA synthesis:
  • Alkylating agents (e.g. nitrogen mustards, nitrosoureas, and methanesulfonate esters)
  • Antifolates (e.g. methotrexate)
  • Antibiotics (e.g. dactinomycin, doxorubicin, and bleomycin)
• Antimetabolites:
  • Purine analogs (e.g. 6-mercaptopurine, 6-thioguanine)
  • Pyrimidine analogs (e.g. 5-fluorouracil, cytarabine)
• Microtubule inhibitors:
  • Vinca alkaloids (e.g. vincristine, vinblastine)
  • Taxanes (e.g. paclitaxel, docetaxel)
• Chromatin function inhibitors:
  • Podophyllotoxins (e.g. etoposide, teniposide)
  • Camptothecin

Alkylating Agents

• Mechanism of action: form covalent bonds with nucleophilic groups in proteins and nucleic acids
• Examples:
  • Nitrogen mustards (e.g. cyclophosphamide, mechlorethamine, chlorambucil, and melphalan)
  • Nitrosoureas (e.g. BCNU, CCNU, and methyl-CCNU)
  • Methane sulfonate esters (e.g. busulfan)
  • Triazenes (e.g. dicarbazine)
  • Ethyleneimines (e.g. triethylenemelamine, triethylenethiophosphamide)

Folic Acid Analogs (Antifolates)

• Mechanism of action: competitive inhibitors of dihydrofolic acid reductase (DHFR)
• Examples:
  • Methotrexate (MTX)
  • Aminopterin
  • Amethoperin

Antimetabolites

• Interfere with nucleic acid biosynthesis
• Examples:
  • Purine analogs (e.g. 6-mercaptopurine, 6-thioguanine)
  • Pyrimidine analogs (e.g. 5-fluorouracil, cytarabine)

Microtubule Inhibitors

• Mechanism of action: bind to microtubules and inhibit their formation or stability
• Examples:
  • Vinca alkaloids (e.g. vincristine, vinblastine)
  • Taxanes (e.g. paclitaxel, docetaxel)

Chromatin Function Inhibitors

• Mechanism of action: inhibit topoisomerase I and II, leading to DNA strand breaks
• Examples:
  • Podophyllotoxins (e.g. etoposide, teniposide)
  • Camptothecin

Immunotherapy

• Monoclonal antibodies (e.g. rituximab, alemtuzumab, gemtuzumab)
• Bispecific antibodies
• Cancer vaccines

Targeted Therapy

• Examples:
  • Tyrosine kinase inhibitors (e.g. gefitinib, trastuzumab)
  • mTOR inhibitors (e.g. temsirolimus)
  • Proteasome inhibitors (e.g. bortezomib)

Traditional CCT vs. Targeted Therapy

• Traditional CCT: non-specific, killing both cancer and normal cells
• Targeted therapy: specific, targeting specific molecules or pathways involved in cancer development and growth