⚛️ Principles & Cytotoxic Kinetics
- Log-kill hypothesis
- Cytotoxic drug effect follows first-order kinetics
- Kills a constant fraction of tumor cells per dose, not a fixed number
- Rationale for combination therapy: multiple agents reduce tumor burden more effectively
- After a dose that kills 99% of cells, remaining 1% can regrow → requires repeated cycles
- Growth fraction
- Proportion of cells actively dividing within a tumor
- High growth fraction → greater sensitivity to cytotoxic drugs
- Normal tissues with high turnover (bone marrow, GI mucosa, hair follicles) are also vulnerable
- Solid tumors often have lower growth fractions → less responsive to cycle-active agents
- Cell-cycle specificity
- Cell-cycle specific (CCS) agents act during particular phases (S, G2, M)
- CCS drugs are most effective against high–growth fraction malignancies (leukemias, lymphomas)
- Cell-cycle nonspecific agents bind DNA and can kill both dividing and resting cells
- Nonspecific drugs are useful for low–growth fraction tumors and as part of combination regimens
High growth fraction
→
CCS drugs more effective
→
Leukemias / lymphomas
Low growth fraction
→
Nonspecific agents preferred
→
Solid tumors
- Bone marrow suppression is the most common dose-limiting toxicity across cytotoxic agents
- Rapidly dividing normal cells (marrow, gut, hair, gonads) share the same vulnerability as tumor cells
💊 Major Anticancer Drug Classes
| Drug | Mechanism | Key Uses | Distinctive Toxicity |
|---|---|---|---|
| Cyclophosphamide | Alkylates guanine N7 → cross-links DNA | Non-Hodgkin, ovarian, breast, neuroblastoma | Hemorrhagic cystitis (acrolein metabolite); mesna protects |
| Cisplatin | Forms DNA cross-links | Testicular, ovarian, bladder, lung | Nephrotoxicity, ototoxicity; amifostine mitigates renal injury |
| Procarbazine | Alkylating agent | Hodgkin lymphoma | Leukemogenic, bone marrow suppression |
| Doxorubicin | Intercalation, free radical formation, topoisomerase inhibition | Hodgkin, breast, endometrial, lung, ovarian | Delayed cardiomyopathy; dexrazoxane (iron chelator) reduces cardiac injury |
| Methotrexate | DHFR inhibitor (S-phase) | Leukemias, lymphomas, breast, rheumatoid arthritis | Bone marrow suppression; leucovorin rescue for overdose |
| 5-Fluorouracil | Thymidylate synthase inhibition (S-phase) | Breast, colorectal, head/neck, topical for skin lesions | Bone marrow suppression, mucositis |
| 6-Mercaptopurine | Purine antimetabolite (S-phase) | Acute lymphocytic leukemia | Bone marrow suppression, hepatotoxicity |
| Bleomycin | Iron-dependent DNA strand scission (G2-phase) | Hodgkin, testicular, head/neck, skin | Pulmonary fibrosis, pneumonitis |
| Vinblastine / Vincristine | Microtubule polymerization inhibitor (M-phase) | Hodgkin, testicular (vinblastine); leukemias, Wilms (vincristine) | Neurotoxicity (especially vincristine) |
| ATRA | Promotes promyelocyte differentiation | Acute promyelocytic leukemia (M3) | Differentiation syndrome (respiratory distress, effusions, CNS symptoms) |
- Capecitabine is an oral prodrug of 5-FU, activated preferentially in tumor tissue
- Thymineless death: 5-FU and flucytosine inhibit thymidylate synthase → nucleotide depletion → cell death
- ATRA differentiation syndrome requires prompt corticosteroid intervention
🎯 Targeted Cancer Therapies
| Agent | Target / Mechanism | Clinical Context |
|---|---|---|
| Imatinib | BCR-ABL tyrosine kinase inhibitor | Chronic myeloid leukemia, GI stromal tumors |
| Cetuximab | Anti-EGFR (ErbB1) monoclonal antibody | Colorectal, head/neck squamous cell carcinoma |
| Trastuzumab | Anti-HER2/neu (ErbB2) mAb | HER2-positive breast cancer |
| Bevacizumab | Anti-VEGF mAb | Colorectal, lung, renal, glioblastoma |
| Sorafenib | RAF kinase inhibitor (multi-kinase) | Hepatocellular, renal cell carcinoma |
- Mechanistic distinctions from cytotoxic agents
- Target specific molecular aberrations rather than all dividing cells
- Often better tolerability profiles, though still have unique toxicities
- Used alone or in combination with traditional chemotherapy
- Resistance mechanisms
- Secondary mutations in target kinase (e.g., T315I in BCR-ABL)
- Upregulation of alternate signaling pathways
- Pharmacokinetic changes (efflux pumps, metabolism)
⚠️ Toxicities & Supportive Care
| Organ System | Offending Agents | Clinical Manifestation |
|---|---|---|
| Renal | Cisplatin, methotrexate | Acute tubular necrosis, crystalluria |
| Pulmonary | Bleomycin, busulfan, procarbazine | Pneumonitis, interstitial fibrosis |
| Cardiac | Doxorubicin, daunorubicin | Dilated cardiomyopathy, heart failure |
| Neurologic | Vincristine, cisplatin | Peripheral neuropathy, ototoxicity |
| Immunosuppression | Cyclophosphamide, methotrexate | Increased infection risk, impaired wound healing |
- Bone marrow suppression
- Neutropenia (granulocytes < 500/mm³) increases infection risk
- Thrombocytopenia (platelets < 20,000/mm³) raises bleeding risk
- Dose adjustments and growth factor support are often required
- Supportive cytokines
- Filgrastim (G-CSF) → stimulates granulocyte production
- Sargramostim (GM-CSF) → increases granulocytes and macrophages
- Erythropoietin → manages anemia (especially renal failure–associated)
- Thrombopoietin → treats thrombocytopenia
- Interleukin-11 → enhances platelet formation
- Aldesleukin (IL-2) → promotes lymphocyte differentiation and NK activity; used in renal cell cancer and melanoma
- Hemorrhagic cystitis from cyclophosphamide is prevented by mesna, which traps the toxic metabolite acrolein
- Dexrazoxane is an iron-chelating agent that reduces doxorubicin-induced free radical formation in cardiac tissue
- Amifostine provides renal protection during cisplatin therapy
🛡️ Immunosuppressants
- Calcineurin inhibitors
- Cyclosporine: binds cyclophilin → inhibits calcineurin → blocks T-cell transcription factors (NFAT) → reduces IL-2, IL-3, IFN-γ
- Tacrolimus: binds FK-binding protein → same calcineurin inhibition pathway
- Primary use: solid organ transplantation (kidney, liver, heart)
- Commonly combined with mycophenolate and/or corticosteroids
- Nephrotoxicity is a major dose-limiting concern for both agents
- Gingival hyperplasia is more characteristic of cyclosporine
- Mycophenolate
- Inhibits de novo purine synthesis → preferentially suppresses lymphocyte proliferation
- Used adjunctively with calcineurin inhibitors to permit lower cyclosporine doses
- Azathioprine
- Prodrug converted to 6-mercaptopurine
- Shares the purine antimetabolite mechanism of action
- Used in transplantation and autoimmune conditions
- Anti-D immunoglobulin
- Human IgG antibodies against the Rh(D) antigen
- Administered to Rh-negative mothers within 72 hours of delivering an Rh-positive infant
- Prevents maternal alloimmunization and hemolytic disease of the newborn in subsequent pregnancies
- Cyclosporine and tacrolimus both cause nephrotoxicity — monitor renal function closely
- Gingival overgrowth is a distinctive side effect of cyclosporine, not tacrolimus
🧬 Monoclonal Antibodies & Cytokines
| Monoclonal Antibody | Mechanism / Target | Clinical Use |
|---|---|---|
| Abciximab | Glycoprotein IIb/IIIa receptor antagonist | Antiplatelet therapy in acute coronary syndromes |
| Infliximab | Anti-TNF-α mAb | Rheumatoid arthritis, Crohn disease, ulcerative colitis |
| Adalimumab | Anti-TNF-α mAb | Rheumatoid arthritis, Crohn disease, psoriasis |
| Trastuzumab | Anti-HER2/neu (ErbB2) mAb | HER2-positive breast cancer |
| Idarucizumab | Dabigatran reversal agent | Emergency reversal of dabigatran anticoagulation |
| Muromonab | Anti-CD3 mAb | Kidney transplant rejection prophylaxis (less common now) |
| Palivizumab | Anti-RSV F protein mAb | Prophylaxis of respiratory syncytial virus in high-risk infants |
| Rituximab | Anti-CD20 mAb | Non-Hodgkin lymphoma, autoimmune disorders |
| Basiliximab | IL-2 receptor antagonist | Prevention of organ transplant rejection |
| Interferon | Clinical Applications |
|---|---|
| Interferon-α | Hepatitis B and C, certain leukemias, melanoma |
| Interferon-β | Multiple sclerosis |
| Interferon-γ | Chronic granulomatous disease (enhances TNF activity) |
- Monoclonal antibody nomenclature: -mab suffix; -ximab (chimeric), -zumab (humanized), -umab (fully human)
- Biosimilars are increasingly available for many mAbs
🧪 Toxic Syndromes & Antidotes
| Poisoning | Key Signs | Intervention / Antidote |
|---|---|---|
| AChE inhibitors | Miosis, salivation, sweating, GI cramps, diarrhea, muscle twitching, seizures | Atropine + pralidoxime (for organophosphates); respiratory support |
| Atropine / anticholinergics | Tachycardia, hyperthermia, dry hot skin, delirium, mydriasis | Physostigmine (crosses BBB); supportive care |
| Carbon monoxide | Nausea, dyspnea, hypotension, syncope, arrhythmias; carboxyHb >10% | Hyperbaric oxygen; 100% humidified O₂ |
| CNS stimulants | Agitation, hyperthermia, tachycardia, hypertension, psychosis, seizures | Benzodiazepines; antipsychotics; control hyperthermia |
| Opioids | Lethargy, bradypnea, miosis, coma, respiratory depression | Naloxone (repeated doses); ventilatory support |
| Salicylates (ASA) | Confusion, hyperventilation, hyperthermia, hypokalemia, metabolic acidosis | Urinary alkalinization; hemodialysis in severe cases |
| Sedative-hypnotics / ethanol | Ataxia, nystagmus, stupor, coma, hypothermia, respiratory failure | Flumazenil (for benzodiazepines); ventilatory support |
| SSRIs | Agitation, confusion, muscle rigidity, hyperthermia, tachycardia, seizures | Cyproheptadine (serotonin antagonist); benzodiazepines; cooling measures |
| Tricyclic antidepressants | Mydriasis, hyperthermia, convulsions, coma, cardiotoxicity (arrhythmias) | Control seizures; correct acidosis; antiarrhythmic support |
- Pralidoxime regenerates AChE only if given before the enzyme ages (usually within 24–48 hours)
- Physostigmine is used for anticholinergic toxicity but is contraindicated in TCA overdose due to risk of arrhythmias
- Flumazenil should be used cautiously in chronic benzodiazepine users due to seizure risk
⛓️ Heavy Metal Poisoning
| Metal | Sources | Clinical Features | Antidote / Management |
|---|---|---|---|
| Arsenic | Wood preservatives, pesticides, ant poisons | Acute: gastroenteritis, hypotension, garlic breath, torsades; Chronic: skin pigmentation, alopecia, neuropathy, myelosuppression | Dimercaprol (BAL); succimer or penicillamine for milder cases |
| Iron | Medicinal supplements, prenatal vitamins | Acute: severe GI distress, hematemesis, bloody diarrhea, shock, coma | Deferoxamine IV; gastric aspiration with carbonate lavage |
| Lead | Paint chips, water pipes, herbal remedies, glazed pottery | Acute: GI pain, encephalopathy; Chronic: anemia (heme synthesis inhibition), neuropathy (wrist drop), nephropathy, cognitive impairment | Dimercaprol (severe), EDTA, succimer (preferred in children), penicillamine |
| Mercury | Instruments, amalgams, dyes, batteries, fireworks | Acute vapor: pneumonitis; Inorganic salt: hemorrhagic gastroenteritis, ATN; Chronic organic: CNS effects, ataxia, paresthesias, visual/auditory loss | Succimer PO or dimercaprol IM; activated charcoal for oral ingestion |
- Dimercaprol (BAL) is contraindicated in iron poisoning and should not be given IV for mercury due to CNS redistribution
- EDTA is a backup agent for lead poisoning and also chelates cadmium, chromium, cobalt, manganese, and zinc
- Penicillamine is used for copper overload (Wilson disease), iron, lead, and mercury chelation
🌿 Natural Medicinals & Supplements
| Agent | Claimed Use | Proposed Mechanism | Key Concerns / Side Effects |
|---|---|---|---|
| Echinacea | Cold symptom reduction | ↑ interleukins, TNF | GI distress, dizziness, headache |
| Garlic | Hyperlipidemia, cancer (weak evidence) | HMG-CoA reductase inhibition, ACE inhibition | Allergy, hypotension, antiplatelet effect → caution with anticoagulants |
| Gingko | Intermittent claudication, Alzheimer (weak evidence) | Antioxidant, free radical scavenger, ↑ NO | Anxiety, GI distress, antiplatelet action → caution with anticoagulants |
| Ginseng | Mental/physical performance (weak evidence) | Unknown | Insomnia, nervousness, hypertension, mastalgia, vaginal bleeding |
| Saw palmetto | Benign prostatic hyperplasia (symptomatic) | 5α-reductase inhibitor, androgen receptor antagonist | GI pain, decreased libido, headache, hypertension |
| St. John's wort | Depression (variable evidence) | Enhances brain serotonin function | Serotonin syndrome with SSRIs; P450 induction → reduces efficacy of many drugs (oral contraceptives, warfarin, statins, etc.) |
- DHEA (dehydroepiandrosterone)
- Androgen precursor; advocated for AIDS, Alzheimer, diabetes, hypercholesterolemia, SLE
- Women: androgenization, cardiovascular concerns, breast cancer risk
- Men: feminization in young; BPH and cancer risk in elderly
- Melatonin
- Serotonin metabolite; used for jet lag and sleep disorders
- Side effects: drowsiness, headache
- Contraindicated in pregnancy, women trying to conceive (↓ LH), and nursing mothers (↓ prolactin)
- Herbal products are not FDA-regulated for safety, efficacy, or purity
- St. John's wort is a potent CYP3A4 inducer → multiple drug interactions
- Garlic and gingko have antiplatelet effects → increase bleeding risk when combined with anticoagulants