Anticancer Drugs

Cancer Chemotherapy

• Case Study: A 55-year-old man with colorectal cancer (CRC) and 5 positive lymph nodes had surgery. Treatment with 5-fluorouracil, leucovorin, and oxaliplatin resulted in severe toxicity including myelosuppression, diarrhea, and altered mental state.
• Fluoropyrimidines: Require dihydropyrimidine dehydrogenase (DPD) for biotransformation. Genetic polymorphisms in DPD can alter biotransformation, possibly explaining the toxicity.
• Percival Pott (1714-1788): A London physician who described and treated compound fractures of the lower fibula and medial malleolus of the tibia with foot dislocation (Pott's Fracture).
• Chimney Sweepers: In 1700, coal was the primary heating source. Narrow chimney flues needed annual cleaning. Young boys were hired to clean the flues.
• Pott (1775): Found cancer of the scrotum in boys (aged 10-14) who worked as chimney sweeps, but not in age-matched controls who lived outside of London. He established a link between the workplace and cancer (tar soot, benzo pyrene).
• Terms:
  • Cancer: Uncontrolled growth of cells, often with invasion into healthy tissues.
  • Malignant: Disease tending towards death.
  • Neoplasia: Formation of tissue.
  • Neoplasm: New or abnormal formation of tissue.
  • Tumor: Swelling.
  • Onco-: Gr. Onkos, bulk or mass.
  • Oncogene: A gene that can induce a cell to become malignant.

Theories of Cancer Causes

• Environmental Exposure: Ionizing radiation.
• Chemical Carcinogen: Azo dyes, aflatoxins, asbestos, tobacco.
• Viruses: Human papillomavirus.

Treatment Modalities

• Chemotherapy Alone: Cures only about 10–15% of cancers.
• Increased Cure Rates Require: Surgery, radiation, and chemotherapy.

Treatment Modalities (Further details)

• 1. Primary Induction Chemotherapy: For widespread systemic diseases like Hodgkin's lymphoma.
• 2. Neoadjuvant Chemotherapy: For localized cancers such as breast, bladder cancer, etc.
• 3. Adjuvant Chemotherapy: Used along with surgery and radiation. This is a common treatment.

Anticancer Drugs

• Action: Can act on cells during cell cycling or in the resting phase.
• Kinetics: Follow first-order kinetics (kill a constant proportion of cells, instead of a constant number).
• Dosing: Based on log kill function. A 3-log dose decreases cell population from 10¹² to 10⁹ cells.
• Examples: cyclophosphamide, cisplatin, methotrexate, leucovorin, mercaptopurine, vinblastine, paclitaxel, bleomycin, imatinib, cetuximab, tamoxifen, fluorouracil, procarbazine.

Cell Cycles

• G₀: Resting phase (many anticancer drugs).
• G₁: Synthesis phase, components for DNA synthesis.
• S: DNA synthesis.
• G₂: Synthesis of components for mitosis.
• M: Mitosis.

Cell Cycle Specific Drugs

• Examples:
  • Antimetabolites
  • Podophyllotoxins
  • Bleomycin
  • Vinca alkaloids.

Non-Cell Cycle Specific Drugs:

• Act in resting (G₀) and all other phases.

Drug Combinations

• (a) Maximize cell kill.
• (b) Increase coverage for heterogeneous tumor types.
• (c) Slow or prevent drug resistance (same as antibiotic chemotherapy).

Mechanisms of Resistance

• 1. Increased DNA Repair: (cisplatin and most alkylating agents).
• 2. Formation of Trapping Agents: Increased glutathione synthesis (binds to anticancer drugs).
• 3. Change in Target Enzymes: Enzyme target becomes less sensitive to drug inhibition.
• 4. Decreased Activation of Prodrugs: Decreased activity of enzymes to convert prodrugs to active drugs.
• 5. Inactivation of Drugs: Increased activity of drug inactivating enzymes.
• 6. Decreased Drug Accumulation: Increased expression of multi-drug transporter (MDR).

Alkylating Agents

• Target: DNA, intercalate with DNA and lead to cell death.

• Examples: cyclophosphamide, nitrogen mustards (chlorambucil, mechlorethamine), nitrosoureas (carmustine, lomustine), alkyl sulfonates (busulfan), cisplatin, procarbazine.

  • Resistance: Increased expression of DNA repair enzymes. Reduced drug transport into the cell. Increase glutathione levels.

• Mechanism of Action: Direct-acting on DNA; Phase I CYP450 required for activation of some to a metabolite (e.g. cyclophosphamide).

• Wide range of Clinical uses: breast, ovarian, neuroblastomas, bladder etc.

Cisplatin

• Inorganic platinum analog.
• Binding to DNA blocks replication.
• Adverse drug reactions (ADRs): nausea, vomiting, peripheral neuropathy, nephrotoxicity, ototoxicity, etc.
• Free radical generation: Procarbazine forms hydrogen peroxide which causes free radicals, resulting in DNA strand scission.

Procarbazine

• Orally active with wide tissue distribution.
• Alkylating agent with a different MOA.
• Used primarily for Hodgkin's Disease
• Major ADRs: Myelosuppressant, GI irritant, CNS dysfunction, peripheral neuropathy, skin reactions.

Antimetabolites

• Drugs are cell cycle-specific inhibitors.
• Resemble endogenous compounds, acting as antagonists to systems that use those compounds.
• All are antagonists of either folic acid (methotrexate), purines (mercaptopurines, thioguanine), or pyrimidines (fluorouracil, cytarabine).

Methotrexate

• Inhibits dihydrofolate reductase (an enzyme that activates folate).
• Antimetabolite acting as a sulfa drug.
• Blocks folate synthesis in cancer cells (and other cells).
• Resistance: Reduced drug transport into the cell. Decreasing cytotoxic drug metabolites. Increasing expression of reductase enzyme. Decreasing enzyme affinity.

Leucovorin

• Rescue drug given with high dose methotrexate to reduce toxicity (myelosuppression).

Mercaptopurine (6-MP)

• Purine antimetabolite activated by hypoxanthine-guanine phosphoribosyltransferase (to toxic nucleotide).
• Inhibits enzymes involved in purine metabolism.
• A thiopurine analog that needs activation to a monophosphate form.

Fluorouracil (5-FU)

• Converted into a metabolite that inhibits thymidylate synthase, causing cell death.

Plant Alkaloids

• Cell-cycle selective drugs.
• Vinca alkaloids (vinblastine) block mitotic spindle formation by preventing tubulin dimers in microtubules.
• Taxanes (paclitaxel) block mitotic spindle through inhibition of microtubule disassembly into tubulin monomers.

Bleomycin

• Cell cycle-selective (G₂ phase) drug.
• Generates free radicals and causes DNA strand breaks.

Hormonal Agents

• Certain cancers require steroid hormones for continued growth. Tumors produce receptors for steroids. Measuring estrogen and progesterone receptors is standard practice. Hormone therapy is not effective on ER/PR receptor-negative cancers.

Tamoxifen

• Drug is an antagonist at estrogen receptors on tumors.

Enzyme Inhibitors and Antibodies

• A wide range of drugs, targeting enzymes and metabolic pathways to shut down cancer cell growth.

Imatinib

• Inhibitor of tyrosine kinase.
• Prevents phosphorylation and activation of the Bcr-Abl oncogene.
• Used in the treatment of chronic myelogenous leukemia.

Growth Factor Receptor Inhibitors

• Many solid tumors overexpress epidermal growth factor receptors (EGFR).
• Blocking these receptors prevents angiogenesis.
• Examples include Cetuximab (a monoclonal antibody).

Cancer Chemotherapy: Drug Selection

• Only active against cancer cells.
• Different mechanisms of action for combined drugs.
• Minimal cross-resistance.
• Different toxic effects to avoid cumulative effects.

Cancer Chemotherapy: Drug Usage

• Pulse therapy: High doses for short periods (to allow the body to recover).
• Recruitment: Cell cycle-selective drugs cause increased levels of cell death and recruit resting cells into cell division (to target actively dividing cells).
• Synchrony: Use drugs to stop cells in M or S phase.
• Rescue Therapy: Reverse side effects of anticancer drugs using drugs like leucovorin (rescuing cells by providing target of the toxic agent given earlier).

The First Tumor Marker (1846)

• Bence Jones proteins in urine precipitate (in acidic solutions).
• Now recognized as light chains from immunoglobulins overproduction by plasma cells (multiple myeloma).

Tumor Markers

• Substances present in or produced by tumors or the host in response to tumors.
• Used to determine tumor presence in blood or secretions.
• Tumors resemble fetal tissues morphologically.

Tumors

• Graded based on differentiation: Well-, poorly differentiated, and anaplastic.
• Tumor markers are re-expressions of substances produced by embryogenically related tissues.

Tumor Markers Classification

• Enzymes: Catalytic activity vs. mass.
• Hormones: Immunoassay.
• Oncofetal Antigens: AFP, CEA, PSA.
• Tumor Antigen Cell Surface Markers: CA 125, CA 15-3, CA 19-9.

Applications of Tumor Markers

• Screening general population.
• Differential diagnosis in symptomatic patients.
• Clinical staging in cancer.
• Estimating tumor volume.
• Evaluating treatment outcomes.
• Detecting recurrence.
• Monitoring therapy response.
• Guiding immunotherapy.

Prostate-Specific Antigen (PSA)

• Protease enzyme found in prostate tissue.
• Discovered in 1971.
• MW 28,430 single chain glycoprotein.
• Bound and free forms in serum.

Human Chorionic Gonadotropin (hCG)

• Glycoprotein produced by the placenta.
• Used for pregnancy detection.
• Alpha and beta subunits.
• Elevated levels can indicate germ cell tumors.

Oncofetal Proteins

• Proteins produced in normal fetal tissues, elevated levels in later life suggest reactivated genes.
• Alpha feto protein (AFP), carcinoembryonic antigen (CEA)
• Levels are high at birth and decline. Elevated levels later in life can indicate cancer development.

Alpha-fetoprotein (AFP)

• Liver and germ cell carcinoma marker.
• Glycoprotein, single polypeptide chain.
• High levels at birth, lower in adults.
• Elevated levels can indicate incomplete tumor removal after surgery (liver tumor).

Carcinoembryonic Antigen (CEA)

• Marker for colorectal, GI, lung and breast cancers.
• Single glycoprotein polypeptide chain.
• Elevated levels in many non-cancer conditions.
• Primarily used to monitor therapy and recurrence.

Carbohydrate Markers

• Either antigens on tumor cell surfaces or secreted by the tumor cell.
• Tend to be more specific than hormones or enzymes.
• Examples include CA 15-3, CA 549, CA 19-9, CA 19-5, CA 72-4, and CA 50.