Anticancer Drugs (Pharmacology

Cheatsheet Content

### Introduction to Anticancer Drug Development The journey from concept to market for a new drug is arduous: - **Discovery & Preclinical Research:** Identify candidates, initial efficacy/safety (toxicology, pharmacokinetics in animals). - **Clinical Trials:** - **Phase I:** Safety, dosage in healthy volunteers/small patient group. - **Phase II:** Efficacy, side effects in larger patient group. - **Phase III:** Confirm efficacy, monitor side effects, compare to standard treatments in large patient group. - **Regulatory Review & Approval:** Submission to agencies (e.g., FDA, EMA). - **Post-Market Surveillance:** Ongoing monitoring for long-term safety/effectiveness. ### Terminology in Cancer Treatment - **Curative Treatment:** Aims for complete cancer eradication. - **Palliative Treatment:** Focuses on symptom relief and quality of life, not cure. - **Position in Treatment Schedule:** - **Neoadjuvant:** Before primary treatment (e.g., surgery) to shrink tumor. - **Adjuvant:** After primary treatment to eliminate residual cells and prevent recurrence. - **Radiochemotherapy:** Radiation + chemotherapy given concurrently. - **Intracavital Chemotherapy:** Administered directly into a body cavity (e.g., peritoneal, bladder). ### Chemotherapy: Basics & Side Effects Chemotherapy uses drugs to stop cancer cell growth (kill or prevent division). Administration routes: oral, injection, infusion, topical. #### Dosage Calculation - **Body Surface Area (BSA):** Most common for chemotherapy, measured in $m^2$. - **Body Weight:** Measured in kg. #### High Yield Side Effects (Categorized) **Early Side Effects (Acute):** - **Hematological:** Myelosuppression (neutropenia, anemia, thrombocytopenia) - **HIGHEST YIELD** - **Gastrointestinal:** Nausea, vomiting, diarrhea, mucositis, stomatitis - **HIGH YIELD** - **Organ Specific:** - Pneumonitis (lungs) - Nephrotoxicity (kidneys) - Urotoxicity (bladder, e.g., hemorrhagic cystitis with cyclophosphamide) - Neurotoxicity (peripheral neuropathy, e.g., vinca alkaloids, taxanes, cisplatin) - Rash **Late Side Effects (Chronic):** - **Cardiomyopathy:** (e.g., anthracyclines) - **HIGH YIELD** - **Secondary Malignancies:** (e.g., alkylating agents, topoisomerase inhibitors) - **HIGH YIELD** - **Gonadal Infertility:** (e.g., alkylating agents) - Immunosuppression - Fibrosis (tissue scarring) ### Classification of Anticancer Drugs 1. **Cytostatics:** Kill or inhibit cancer cell growth (traditional chemotherapy). - Alkylating Agents - Antimetabolites (Pyrimidine, Purine, Antifolates) - Cytotoxic Antibiotics (Anthracyclines, Bleomycin) - Mitotic Inhibitors (Taxanes, Vinca Alkaloids) - Topoisomerase Inhibitors 2. **Hormonal Agents:** Interfere with hormone production/action (e.g., breast, prostate cancer). 3. **Monoclonal Antibodies (mAbs):** Target specific cancer cell proteins. 4. **Protein Kinase Inhibitors (TKIs):** Block activity of kinases in signaling pathways. 5. **Targeted Therapy:** Broad category, specific molecular targets (includes mAbs & TKIs). 6. **Immunotherapy:** (Missing from lecture, **HIGH YIELD**) Boosts body's immune system to fight cancer. - **Checkpoint Inhibitors:** Block inhibitory pathways (e.g., anti-PD-1, anti-CTLA-4). - **CAR T-cell Therapy:** Genetically engineered T-cells. 7. **Supportive Care:** Manage side effects. 8. **Isotopes:** Radioactive substances. ### Cytostatics: Detailed Mechanisms & Examples #### 1. Alkylating Agents - **Mechanism:** Form covalent bonds with DNA (alkylation), inhibiting DNA transcription, replication, and repair. Primarily active in rapidly dividing cells. Can lead to cross-linking DNA. - **Toxicity:** Cytotoxic, mutagenic, carcinogenic. Myelosuppression, secondary malignancies. - **High Yield Examples:** - **Cyclophosphamide:** - **Indications:** Broad spectrum (leukemias, lymphomas, solid tumors, autoimmune). - **Key Side Effects:** Hemorrhagic cystitis (prevent with mesna), myelosuppression, alopecia, GI upset. - **Platinum-Containing Agents (Cisplatin, Carboplatin, Oxaliplatin):** - **Mechanism:** Cross-link DNA, inducing apoptosis. - **Cisplatin:** - **Indications:** Testicular, ovarian, bladder cancer. - **Key Side Effects:** Nephrotoxicity (prevent with hydration), ototoxicity, severe nausea/vomiting, peripheral neuropathy. - **Carboplatin:** Less nephrotoxic/ototoxic than cisplatin, more myelosuppressive. - **Oxaliplatin:** Peripheral neuropathy (cold-induced). - **Other Examples:** Nitrogen Mustards (Mechlorethamine, Melphalan, Chlorambucil), Nitrosoureas (Carmustine, Lomustine - cross blood-brain barrier), Busulfan, Dacarbazine. #### 2. Antimetabolites - **Mechanism:** Structurally similar to natural metabolites, interfere with DNA/RNA synthesis. - **Sub-types:** a. **Pyrimidine Analogues:** (e.g., 5-Fluorouracil (5-FU), Gemcitabine, Cytarabine) - **5-FU:** - **Mechanism:** Inhibits thymidylate synthase (decreases dTMP production), incorporated into DNA/RNA. - **Indications:** GI cancers (colorectal), breast cancer. - **Key Side Effects:** Myelosuppression, mucositis, hand-foot syndrome, diarrhea. Enhanced by leucovorin. - **Gemcitabine:** Inhibits ribonucleotide reductase, incorporated into DNA. Pancreatic, lung, breast, ovarian. - **Cytarabine:** (Ara-C) Leukemias. Myelosuppression, cerebellar toxicity. b. **Antifolates:** (e.g., Methotrexate (MTX)) - **Mechanism:** Inhibits dihydrofolate reductase (DHFR), preventing synthesis of tetrahydrofolate (essential for purine/pyrimidine synthesis). - **Indications:** Leukemias, lymphomas, solid tumors, autoimmune diseases, ectopic pregnancy. - **Key Side Effects:** Myelosuppression, mucositis, nephrotoxicity (high dose), hepatotoxicity. **Leucovorin rescue** is critical for high-dose MTX to prevent toxicity. c. **Purine Analogues:** (e.g., Fludarabine, Mercaptopurine) - **Mechanism:** Incorporated into DNA/RNA. - **Fludarabine:** CLL. Immunosuppression (risk of opportunistic infections). #### 3. Cytotoxic Antibiotics - **Mechanism:** Diverse, often intercalate DNA, inhibit topoisomerases or generate free radicals. - **High Yield Examples:** - **Anthracyclines (Doxorubicin, Daunorubicin, Epirubicin):** - **Mechanism:** Intercalate DNA, inhibit Topo II, generate free radicals. - **Indications:** Broad spectrum (leukemias, lymphomas, solid tumors). - **Key Side Effects:** **Cardiotoxicity (dose-dependent, cumulative)** - **HIGH YIELD**, myelosuppression, mucositis, alopecia, red urine. - **Dexrazoxane:** Cardioprotectant. - **Bleomycin:** - **Mechanism:** Induces DNA strand breaks. - **Indications:** Testicular cancer, Hodgkin lymphoma. - **Key Side Effects:** **Pulmonary fibrosis** - **HIGH YIELD**, hypersensitivity reactions. Minimal myelosuppression. #### 4. Mitotic Inhibitors - **Mechanism:** Target microtubules, essential for cell division. - **Sub-types:** a. **Taxanes (Paclitaxel, Docetaxel):** - **Mechanism:** Stabilize microtubules, preventing depolymerization and disassembly (freezing cells in metaphase). - **Indications:** Ovarian, breast, lung cancer. - **Key Side Effects:** Peripheral neuropathy, myelosuppression, hypersensitivity reactions (premedication required), fluid retention (docetaxel). b. **Vinca Alkaloids (Vincristine, Vinblastine, Vinorelbine):** - **Mechanism:** Bind to tubulin, preventing microtubule assembly (inhibiting polymerization). - **Indications:** Leukemias, lymphomas, solid tumors. - **Vincristine:** **Neurotoxicity (peripheral neuropathy, constipation)** - **HIGH YIELD**, less myelosuppression. - **Vinblastine:** More myelosuppression, less neurotoxicity. #### 5. Topoisomerase Inhibitors - **Mechanism:** Target topoisomerase enzymes, critical for DNA replication and transcription. - **Sub-types:** - **Topoisomerase I Inhibitors (Irinotecan, Topotecan):** - **Mechanism:** Stabilize Topo I-DNA cleavable complex, causing DNA strand breaks. - **Irinotecan:** Colorectal cancer. - **Key Side Effects:** Severe diarrhea (early & delayed - **HIGH YIELD**), myelosuppression. Early diarrhea treated with atropine, delayed with loperamide. - **Topoisomerase II Inhibitors (Etoposide, Teniposide):** - **Mechanism:** Stabilize Topo II-DNA cleavable complex, causing double-strand breaks. - **Etoposide:** Lung cancer, lymphomas. - **Key Side Effects:** Myelosuppression, secondary leukemias. ### Hormonal Agents - **Mechanism:** Interfere with hormone production or action, primarily for hormone-sensitive cancers (breast, prostate). - **High Yield Examples:** - **Antiestrogens (Tamoxifen):** - **Mechanism:** Selective Estrogen Receptor Modulator (SERM). Antagonist in breast tissue, agonist in bone/uterus. - **Indications:** Estrogen Receptor-positive breast cancer (treatment and prevention). - **Key Side Effects:** Hot flashes, increased risk of endometrial cancer, thromboembolism. - **Aromatase Inhibitors (Anastrozole, Letrozole, Exemestane):** - **Mechanism:** Block estrogen synthesis from androgens (primarily in postmenopausal women). - **Indications:** ER-positive breast cancer (postmenopausal). - **Key Side Effects:** Musculoskeletal pain, increased risk of osteoporosis. - **Antiandrogens (Bicalutamide, Enzalutamide):** - **Mechanism:** Block androgen receptors. - **Indications:** Prostate cancer. - **GnRH Analogues (Leuprolide, Goserelin):** - **Mechanism:** Initially stimulate, then downregulate GnRH receptors, suppressing LH/FSH and thus testosterone/estrogen. - **Indications:** Prostate cancer, breast cancer (premenopausal). - **Key Side Effects:** "Flare" reaction initially, then hot flashes, decreased libido, osteoporosis. ### Targeted Therapies: mAbs & Kinase Inhibitors - **Mechanism:** Highly specific, target molecular pathways critical for cancer growth/survival, often with fewer systemic side effects than traditional chemo. #### 1. Monoclonal Antibodies (mAbs) - **Mechanism:** Bind specific antigens on cancer cells or in the tumor microenvironment. - **High Yield Examples:** - **Trastuzumab (Herceptin):** - **Target:** HER2 receptor. - **Indications:** HER2-positive breast cancer, gastric cancer. - **Key Side Effects:** **Cardiotoxicity**, infusion reactions. - **Rituximab:** - **Target:** CD20 on B-cells. - **Indications:** Non-Hodgkin lymphoma, CLL, autoimmune diseases. - **Key Side Effects:** Infusion reactions, immunosuppression (PML risk). - **Bevacizumab (Avastin):** - **Target:** VEGF (Vascular Endothelial Growth Factor). - **Mechanism:** Inhibits angiogenesis (new blood vessel formation), "starving" tumor. - **Indications:** Colorectal, lung, renal, glioblastoma. - **Key Side Effects:** Hypertension, bleeding, impaired wound healing, proteinuria, GI perforation. - **Cetuximab, Panitumumab:** - **Target:** EGFR (Epidermal Growth Factor Receptor). - **Indications:** Colorectal, head & neck cancer (KRAS wild-type). - **Key Side Effects:** Acne-like rash, infusion reactions, diarrhea. #### 2. Protein Kinase Inhibitors (Small Molecule Inhibitors) - **Mechanism:** Block ATP binding site or active site of specific kinases. Often oral. - **High Yield Examples:** - **Imatinib (Gleevec):** - **Target:** BCR-ABL tyrosine kinase (Philadelphia chromosome). - **Indications:** Chronic Myeloid Leukemia (CML), GIST. - **Key Side Effects:** Fluid retention (periorbital edema), myelosuppression, GI upset. - **Erlotinib, Gefitinib, Osimertinib:** - **Target:** EGFR tyrosine kinase. - **Indications:** EGFR-mutated non-small cell lung cancer (NSCLC). - **Key Side Effects:** Rash, diarrhea. - **BRAF Inhibitors (Vemurafenib, Dabrafenib):** - **Target:** BRAF V600E mutation. - **Indications:** Melanoma. - **Key Side Effects:** Rash, photosensitivity, arthralgia, secondary cutaneous malignancies (squamous cell carcinoma). - **ALK Inhibitors (Crizotinib, Alectinib):** - **Target:** ALK fusion oncogene. - **Indications:** ALK-rearranged NSCLC. ### Immunotherapy (HIGH YIELD - Crucial Addition) - **Mechanism:** Harnesses the body's own immune system to recognize and destroy cancer cells. - **Key Classes:** - **Immune Checkpoint Inhibitors:** - **Mechanism:** Block inhibitory checkpoints on T-cells (e.g., PD-1, CTLA-4) or their ligands on tumor cells (e.g., PD-L1), allowing T-cells to attack cancer. - **High Yield Examples:** - **Anti-PD-1:** Pembrolizumab, Nivolumab. - **Anti-PD-L1:** Atezolizumab, Durvalumab. - **Anti-CTLA-4:** Ipilimumab. - **Indications:** Melanoma, lung cancer, renal cell carcinoma, Hodgkin lymphoma, many others. - **Key Side Effects (Immune-Related Adverse Events - irAEs):** Due to autoimmune activation. Can affect almost any organ: colitis, pneumonitis, hepatitis, endocrinopathies (thyroiditis, hypophysitis), skin rash. Requires careful management with corticosteroids. - **CAR T-cell Therapy:** - **Mechanism:** Patient's T-cells are genetically engineered to express Chimeric Antigen Receptors (CARs) that target specific antigens on cancer cells (e.g., CD19 for B-cell leukemias/lymphomas). Expanded ex vivo and reinfused. - **Indications:** Refractory B-cell acute lymphoblastic leukemia (ALL), large B-cell lymphoma. - **Key Side Effects:** Cytokine Release Syndrome (CRS) - **HIGH YIELD** (fever, hypotension, hypoxia, organ dysfunction, neurotoxicity), neurotoxicity (ICANS).