Pharmacology CRASH Course — Notes OmpathStudy

WEEK 1: INTRODUCTION TO ONCOLOGY History of cancer treatment: - Ancient era – surgery only (Egyptian/Greek records of tumor excision) Early 1900s – radiotherapy introduced (discovery of X-rays/radium) 1940s – first chemotherapy (nitrogen mustard, derived from WWI chemical warfare research) 1990s–2000s – targeted therapy era (imatinib, trastuzumab) 2010s–present – immunotherapy/checkpoint inhibitors, personalized/precision oncology Cellular and genetic basis of cancer: Cancer = uncontrolled cell proliferation from accumulated genetic mutations Oncogenes – mutated/overactive genes that drive proliferation (e.g. RAS, HER2/neu, MYC) Tumor suppressor genes – normally halt proliferation/induce apoptosis; loss of function drives cancer (e.g. p53, BRCA1/2, RB) DNA repair gene defects – allow mutations to accumulate (e.g. Lynch syndrome – mismatch repair genes) Mechanisms of cancer (Hallmarks of Cancer): Sustained proliferative signaling Evasion of growth suppressors Resistance to apoptosis (cell death evasion) Replicative immortality (telomerase reactivation) Angiogenesis induction (new blood vessel formation) Invasion and metastasis Reprogrammed energy metabolism (Warburg effect) Evasion of immune destruction Cancer biology basics: Tumor = clonal expansion of a single mutated cell Benign vs malignant – malignant cells invade locally and metastasize Grading (differentiation) vs Staging (extent of spread, e.g. TNM system) Immuno-oncology introduction: Immune system can recognize and destroy abnormal cells (immune surveillance) Tumors evade this via immune checkpoints (PD-1/PD-L1, CTLA-4) – basis for modern immunotherapy Tumor microenvironment can be immunosuppressive (Tregs, myeloid-derived suppressor cells) WEEK 2: TREATMENT APPROACHES IN ONCOLOGY Surgery: Curative (complete tumor removal, early-stage solid tumors) Palliative (relieve symptoms, debulking) Diagnostic (biopsy for histology) Reconstructive (post-resection) Radiotherapy: Uses ionizing radiation to damage DNA of rapidly dividing cells External beam vs brachytherapy (internal source) Can be curative, adjuvant (post-surgery), neoadjuvant (pre-surgery to shrink tumor), or palliative (pain/bleeding control) Adverse effects: local skin reactions, fatigue, organ-specific damage (e.g. pneumonitis, fibrosis) Pharmacotherapy (overview): Chemotherapy – cytotoxic drugs targeting dividing cells Hormonal therapy – for hormone-sensitive cancers (breast, prostate) Targeted therapy – molecularly targets specific cancer pathways Immunotherapy – harnesses immune system against tumor Often used in combination (multimodal therapy) for best outcomes WEEK 3: CLASSIFICATION OF CHEMOTHERAPY DRUGS By cell-cycle specificity: Cell-cycle-specific (CCS) – act only on actively dividing cells in a particular phase G1 phase: corticosteroids S phase: antimetabolites (methotrexate, 5-FU) M phase: vinca alkaloids, taxanes More effective against rapidly growing tumors (high growth fraction) Cell-cycle-nonspecific (CCNS) – act on cells in any phase, including resting (G0) Alkylating agents, antitumor antibiotics, platinum compounds Effective against slow-growing tumors too; often more dose-dependent toxicity Cell cycle phases (for reference): G1 (growth) → S (DNA synthesis) → G2 (preparation for division) → M (mitosis) → back to G1 or G0 (resting) Clinical implication: CCS drugs are scheduled based on cell cycle timing (e.g. repeated dosing) CCNS drugs follow a linear dose-response (more drug = more cell kill) regardless of timing WEEK 4: ALKYLATING AGENTS, ANTIMETABOLITES, ANTHRACYCLINES Alkylating agents (CCNS): MOA – form covalent bonds (alkyl groups) with DNA → cross-linking of DNA strands → prevents replication/transcription → apoptosis Examples: Cyclophosphamide – prodrug, activated in liver; used in lymphomas, leukemias, autoimmune disease Carmustine – crosses BBB, used in brain tumors Cisplatin – also classified as platinum compound (see Week 5) Toxicities: myelosuppression, hemorrhagic cystitis (cyclophosphamide – prevented with mesna + hydration), secondary leukemias (long-term risk) Antimetabolites (CCS – S phase): MOA – structurally mimic normal metabolites (folate, purines, pyrimidines) → block DNA/RNA synthesis Examples: Methotrexate – folate antagonist (inhibits dihydrofolate reductase); rescue with leucovorin (folinic acid) to reduce toxicity 5-Fluorouracil (5-FU) – pyrimidine analog, blocks thymidylate synthase Gemcitabine – pyrimidine analog, used in pancreatic, lung cancers Toxicities: mucositis, myelosuppression, hepatotoxicity (methotrexate), hand-foot syndrome (5-FU) Anthracyclines (CCNS): MOA – inhibit topoisomerase II + intercalate into DNA + generate free radicals → DNA strand breaks Examples: Doxorubicin, Daunorubicin, Epirubicin Toxicities: dose-dependent cardiotoxicity (cumulative dose limit, monitor ejection fraction), myelosuppression, alopecia, "red urine" (harmless discoloration) Cardioprotection: dexrazoxane; liposomal formulations reduce cardiotoxicity WEE