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Cancer Pharmacology: Complete USMLE Review

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1. CANCER TREATMENT MODALITIES

• Curative intent (e.g., testicular cancer with BEP, childhood ALL, Hodgkin lymphoma)
• Adjuvant chemotherapy: given after surgery to eliminate micrometastases (e.g., colon cancer FOLFOX)
• Neoadjuvant: given before surgery to shrink tumor
• Palliative: control symptoms in advanced disease

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2. ROLE OF CELL CYCLE KINETICS & ANTICANCER EFFECT

The Cell Cycle

G1 (gap 1) → S (DNA synthesis) → G2 (gap 2) → M (mitosis) → G0 (resting)

• G1: RNA and protein synthesis; preparation for DNA replication
• S phase: DNA replication — target of antimetabolites
• G2: Further protein synthesis, repair; preparation for mitosis
• M phase: Mitosis — target of vinca alkaloids, taxanes
• G0: Quiescent cells; may re-enter cycle; CCNS drugs can still kill these

Cell Cycle-Specific (CCS) vs. Cell Cycle-Nonspecific (CCNS)

• Tumors do NOT grow exponentially; growth fraction decreases as tumor enlarges
• Small tumors grow fast (high growth fraction); large tumors grow slowly
• Implication: chemotherapy is more effective at small tumor burdens (adjuvant setting)
• Growth fraction peaks when tumor is ~1/3 its maximum size

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3. DRUG RESISTANCE

Mechanisms of Resistance

1. Provides maximal cell kill within tolerated toxicity
2. Broader coverage of heterogeneous tumor populations
3. Prevents/delays resistance by multiple simultaneous mechanisms
4. Uses drugs with non-overlapping toxicities to allow full dosing

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4. BASIC PHARMACOLOGY OF CANCER CHEMOTHERAPY DRUGS

General Toxicity Principles

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5. ALKYLATING AGENTS

Nitrogen Mustards

• Uses: CML (historical), bone marrow transplant conditioning
• Unique toxicity: "Busulfan lung" — pulmonary fibrosis; also skin hyperpigmentation, Addison-like syndrome, infertility

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6. NITROSOUREAS

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7. NONCLASSIC ALKYLATING AGENTS

Dacarbazine (DTIC)

• Requires hepatic activation via oxidative N-demethylation to diazomethane
• Uses: Hodgkin lymphoma (ABVD regimen — the D), soft tissue sarcomas, neuroblastoma
• Toxicity: Myelosuppression, severe nausea/vomiting; potent vesicant

Temozolomide

• Oral; spontaneously converts to active alkylating species at physiologic pH (no hepatic activation needed)
• Gold standard for glioblastoma multiforme (Stupp protocol: concurrent radiation + temozolomide, then adjuvant temozolomide)
• Temozolomide efficacy is enhanced in tumors with MGMT promoter methylation (MGMT is the DNA repair enzyme that reverses alkylation; when its gene is silenced by methylation, alkylation damage persists → greater tumor kill)
• Toxicity: Myelosuppression, nausea

Procarbazine

• Inhibits DNA, RNA, and protein synthesis; weakly inhibits MAO
• Part of classic MOPP regimen (now mostly replaced by ABVD for Hodgkin): Mechlorethamine, Oncovin (vincristine), Procarbazine, Prednisone
• Drug interactions: MAO inhibitor → avoid tyramine-rich foods (hypertensive crisis), sympathomimetics, tricyclics, alcohol (disulfiram-like reaction)
• Toxicity: Myelosuppression, peripheral neuropathy, secondary AML

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8. PLATINUM ANALOGS

Cisplatin

• Prototype platinum analog
• Uses: Testicular (BEP — curative), ovarian, bladder, head/neck, lung (NSCLC, SCLC), esophageal, cervical cancers
• Major toxicities (memorize all four):
  1. Nephrotoxicity — proximal tubular necrosis (prevent with aggressive IV hydration + amifostine; monitor creatinine)
  2. Peripheral sensory neuropathy — "stocking-glove" distribution; cumulative and dose-dependent
  3. Ototoxicity — high-frequency hearing loss (irreversible; audiometry monitoring needed)
  4. Severe nausea/vomiting — most emetogenic chemo drug; requires prophylactic 5-HT3 antagonist + NK1 antagonist (aprepitant)
• Myelosuppression is less prominent than with other platinum analogs
• Eliminated renally → dose reduce in renal failure

Carboplatin

• Second-generation; replaces cisplatin in many regimens due to better tolerability
• Less: nephrotoxicity, neurotoxicity, ototoxicity, nausea
• More: myelosuppression (thrombocytopenia > neutropenia) — dose-limiting toxicity
• Uses: Ovarian cancer (first-line with paclitaxel), NSCLC, others
• Dosed by AUC (Calvert formula) using GFR

Oxaliplatin

• Third-generation; combined with 5-FU/leucovorin as FOLFOX for colorectal cancer
• Unique toxicity: Peripheral neuropathy — acute cold-triggered dysesthesias (hands/feet/throat feel strange when touching cold objects; tell patients to avoid cold) and cumulative sensory neuropathy
• Less nephrotoxicity than cisplatin; minimal ototoxicity
• No cross-resistance with cisplatin

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9. ANTIMETABOLITES — ANTIFOLATES

Methotrexate (MTX)

• Mechanism: Inhibits dihydrofolate reductase (DHFR) → prevents conversion of dihydrofolate → tetrahydrofolate → blocks synthesis of thymidylate and purines → inhibits DNA synthesis
• Uses (broad — memorize):
  • Oncologic: ALL (induction + maintenance + CNS prophylaxis via intrathecal MTX), osteosarcoma, breast cancer, head/neck cancer, choriocarcinoma (curative as single agent!), bladder cancer
  • Non-oncologic: Rheumatoid arthritis, psoriasis, ectopic pregnancy, medical abortion, SLE, inflammatory bowel disease
• Toxicities: Myelosuppression, mucositis/stomatitis, hepatotoxicity (fibrosis with chronic use), nephrotoxicity at high doses (MTX precipitates in renal tubules — alkalinize urine), teratogenic (avoid in pregnancy), pneumonitis
• Leucovorin (folinic acid) rescue: Given 24 hours after high-dose MTX to rescue normal cells (provides reduced folate that bypasses DHFR). Essential in high-dose protocols.
• Resistance: Increased DHFR expression, decreased drug uptake (reduced folate carrier mutations), increased efflux

Pemetrexed

• Inhibits DHFR, thymidylate synthase (TS), and GARFT (multiple folate-dependent enzymes)
• Uses: Mesothelioma (first-line with cisplatin), non-squamous NSCLC
• Toxicity: Myelosuppression, mucositis (must supplement folic acid + B12 to reduce toxicity)

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10. FLUOROPYRIMIDINES

5-Fluorouracil (5-FU)

• Mechanism:
  1. Active metabolite FdUMP irreversibly inhibits thymidylate synthase (TS) → blocks dTMP synthesis → "thymineless death" (most important mechanism)
  2. FUTP incorporated into RNA → impairs RNA processing and function
• Leucovorin (folinic acid) enhances 5-FU activity — stabilizes the FdUMP-TS-folate ternary complex
• CCS (S-phase)
• Uses: Colorectal cancer (FOLFOX, FOLFIRI, CAPOX), breast cancer (CMF), head/neck cancer, gastric cancer, pancreatic cancer
• Toxicities:
  • Myelosuppression (bolus schedule)
  • Mucositis/diarrhea (infusion schedule)
  • Hand-foot syndrome (palmar-plantar erythrodysesthesia) — continuous infusion
  • Cerebellar ataxia (rare but classic USMLE question)
  • Coronary vasospasm (rare)
• DPD (dihydropyrimidine dehydrogenase) deficiency: DPD is the main enzyme that catabolizes 5-FU. Patients with DPD deficiency have severe, life-threatening toxicity from standard doses — the basis of the case study in Katzung (altered mental status, myelosuppression, diarrhea after first FOLFOX cycle). Test with genetic testing.

Capecitabine

• Oral prodrug of 5-FU; converted to 5-FU preferentially in tumor tissue by thymidine phosphorylase (overexpressed in tumors)
• Uses: Colorectal cancer (CAPOX regimen), breast cancer, gastric cancer
• Unique toxicity: Hand-foot syndrome more prominent than IV 5-FU

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11. DEOXYCYTIDINE ANALOGS

Cytarabine (Ara-C, cytosine arabinoside)

• Mechanism: Phosphorylated to ara-CTP → incorporated into DNA → DNA chain termination; also inhibits DNA polymerase
• CCS (S-phase)
• Uses: AML (cornerstone of induction — "7+3" regimen: 7 days continuous cytarabine + 3 days daunorubicin/idarubicin); ALL, CML blast crisis
• Toxicities:
  • Standard dose: Myelosuppression, mucositis, nausea
  • High-dose Ara-C: Cerebellar toxicity (ataxia, dysarthria — check for nystagmus before each dose), conjunctivitis (treat with steroid eye drops)
• Ara-C syndrome: Fever, myalgias, bone pain 6–12 hours after administration

Gemcitabine

• Deoxycytidine analog with much broader activity than cytarabine (active in solid tumors)
• Mechanism: Incorporated into DNA → chain termination; also inhibits ribonucleotide reductase
• Uses: Pancreatic cancer (first-line), NSCLC, bladder cancer, ovarian cancer (second-line), soft tissue sarcoma
• Toxicity: Myelosuppression (neutropenia dose-limiting), nausea, flu-like syndrome, rare HUS/TTP
• Eliminated renally

Azacitidine & Decitabine

• Hypomethylating agents — incorporate into DNA and inhibit DNA methyltransferase → gene re-expression (epigenetic therapy)
• Uses: Myelodysplastic syndrome (MDS), AML (older patients not candidates for intensive therapy)

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12. PURINE ANTAGONISTS

6-Mercaptopurine (6-MP)

• Requires activation by HGPRT (hypoxanthine-guanine phosphoribosyl transferase) → 6-thioinosinic acid → inhibits purine nucleotide synthesis
• Uses: ALL maintenance therapy (with methotrexate — years of maintenance)
• Azathioprine is a prodrug that is converted to 6-MP in vivo (used as immunosuppressant)
• Key interaction: Allopurinol (xanthine oxidase inhibitor used in tumor lysis syndrome prophylaxis) blocks 6-MP metabolism → reduce 6-MP dose by 50–75% when giving with allopurinol (or use 6-TG instead)
• TPMT (thiopurine S-methyltransferase) polymorphisms: TPMT inactivates thiopurines. Low TPMT activity (homozygous recessive) → severe toxicity with standard doses of 6-MP/azathioprine

6-Thioguanine (6-TG)

• Similar mechanism; used in AML
• Unlike 6-MP, NOT significantly metabolized by xanthine oxidase → no allopurinol dose adjustment needed with 6-TG

Fludarabine

• Purine nucleoside analog; phosphorylated to F-ara-ATP → inhibits DNA polymerase, induces apoptosis
• Uses: CLL (FCR regimen: Fludarabine + Cyclophosphamide + Rituximab), low-grade NHL, hairy cell leukemia
• Toxicity: Myelosuppression, profound immunosuppression (CD4/CD8 T cell depletion → opportunistic infections; CMV reactivation); autoimmune hemolytic anemia

Cladribine (2-CDA, 2-chlorodeoxyadenosine)

• High specificity for lymphoid cells
• Uses: Hairy cell leukemia (drug of choice — single 7-day infusion can induce durable complete remission), CLL, low-grade NHL
• Toxicity: Transient myelosuppression; prolonged immunosuppression (CD4/CD8 depletion for >1 year)

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13. NATURAL PRODUCT DRUGS — VINCA ALKALOIDS

• Vincristine = Constipation + Cranial nerve palsies + peripheral neuropathy (C's)
• Vinblastine = Bone marrow suppression

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14. TAXANES & OTHER ANTI-MICROTUBULE DRUGS

Paclitaxel (Taxol)

• Derived from Pacific yew tree (Taxus brevifolia)
• Uses: Ovarian cancer (first-line with carboplatin), breast cancer, NSCLC, head/neck cancer, gastric cancer, prostate (Kaposi)
• Toxicities:
  • Peripheral neuropathy (dose-limiting; sensory > motor)
  • Myelosuppression (neutropenia)
  • Hypersensitivity reactions (due to Cremophor EL solvent) → must premedicate with dexamethasone + diphenhydramine + H2 blocker before each infusion
  • Bradycardia/heart block (rare)
  • Alopecia

Docetaxel (Taxotere)

• Similar mechanism; more potent
• Uses: Breast, NSCLC, prostate (with prednisone), gastric cancer
• Unique toxicities: Fluid retention/edema (cumulative; use dexamethasone prophylaxis), nail changes, more severe myelosuppression

Nab-Paclitaxel (Abraxane)

• Albumin-bound paclitaxel nanoparticle — no Cremophor → no hypersensitivity premedication needed
• Uses: Pancreatic cancer (+ gemcitabine), breast, NSCLC

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15. CAMPTOTHECINS (TOPOISOMERASE I INHIBITORS)

Irinotecan (CPT-11)

• Prodrug → converted by carboxylesterase to SN-38 (1000× more potent than parent drug)
• Uses: Colorectal cancer (FOLFIRI: irinotecan + 5-FU + leucovorin); pancreatic cancer (liposomal irinotecan)
• Classic toxicities:
  • Early diarrhea (within 24 hours): cholinergic mechanism (excess acetylcholine) → treat with atropine
  • Late diarrhea (2–10 days post-infusion): secretory mechanism → treat with high-dose loperamide; can be severe/life-threatening
  • Myelosuppression
• UGT1A1 polymorphism: UGT1A1 glucuronidates SN-38 for excretion. UGT1A1*28 variant (homozygous) → reduced SN-38 clearance → severe toxicity

Topotecan

• Uses: Ovarian cancer (second-line after platinum failure), SCLC (second-line)
• Eliminated renally (unlike irinotecan which is hepatic/biliary)
• Toxicity: Myelosuppression

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16. ANTITUMOR ANTIBIOTICS — ANTHRACYCLINES

1. Inhibit topoisomerase II → double-strand DNA breaks
2. Generate free radicals (semiquinone) → DNA strand scission (also causes cardiotoxicity)
3. Intercalate into DNA → block DNA/RNA synthesis
4. Bind cell membranes → alter ion transport

Cardiotoxicity — HIGH YIELD

• Cumulative dose-dependent dilated cardiomyopathy (most important toxicity)
• Doxorubicin: Maximum cumulative dose 450–550 mg/m² (lifetime limit)
• Mechanism: Free radical damage to myocardial cells (iron-doxorubicin complex generates hydroxyl radicals)
• Prevention: Dexrazoxane (iron chelator — sequesters iron, prevents free radical formation) — use when cumulative doxorubicin dose exceeds 300 mg/m²
• Monitoring: Echocardiography (LVEF) at baseline and during therapy
• Acute cardiotoxicity (rare): Arrhythmias during infusion
• Mnemonic: Doxorubicin → Dilated cardiomyopathy → Dexrazoxane protects

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17. MITOMYCIN

• Isolated from Streptomyces caespitosus
• Mechanism: Bioreductive alkylating agent — undergoes enzymatic reduction in hypoxic environments → generates reactive species → interstrand DNA cross-links (alkylation)
• Uses: Bladder cancer (intravesical — direct installation into bladder; standard of care for superficial bladder cancer), anal cancer (with 5-FU), gastric cancer, cervical cancer
• Toxicities:
  • Myelosuppression (delayed, cumulative)
  • Hemolytic Uremic Syndrome (HUS) — thrombotic microangiopathy; cumulative dose-related; serious
  • Pulmonary fibrosis
  • Vesicant

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18. BLEOMYCIN

• Mixture of glycopeptide antibiotics from Streptomyces verticillus
• Mechanism: Binds DNA + Fe²⁺ → generates free radicals → single- and double-strand DNA breaks → cell death
• CCS (G2/M phase)
• Minimal myelosuppression — key fact (bleomycin is one of the few chemo agents that does NOT significantly suppress the bone marrow)
• Uses: Testicular cancer (BEP: Bleomycin + Etoposide + cisPlatin — curative even in metastatic disease), Hodgkin lymphoma (ABVD — the B)
• Toxicities:
  • Pulmonary fibrosis — DOSE-LIMITING; cumulative dose-dependent (monitor with PFTs — reduced DLCO is earliest sign); risk increased with >400 units total dose, age >70, renal failure, prior chest radiation
  • Skin toxicity: hyperpigmentation, thickening, Raynaud phenomenon
  • Mucositis, alopecia
  • Hypersensitivity/fever reactions (especially in lymphoma patients)
  • High FiO2 worsens pulmonary toxicity — critical USMLE pearl: minimize O2 during anesthesia for patients who received bleomycin (avoid FiO2 >30% intraoperatively)

• BEP = best regimen for testicular cancer
• ABVD = Adriacin (doxorubicin) + Bleomycin + Vinblastine + Dacarbazine = standard Hodgkin
• Bleomycin = pulmonary fibrosis (think: "Bleo-your lungs")

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19. MISCELLANEOUS ANTICANCER DRUGS

Hydroxyurea

• Mechanism: Inhibits ribonucleotide reductase → blocks conversion of ribonucleotides to deoxyribonucleotides → inhibits DNA synthesis. CCS (S-phase).
• Uses: CML (historical, now replaced by imatinib), sickle cell disease (increases HbF production), polycythemia vera, essential thrombocythemia
• Toxicity: Myelosuppression, mucositis, skin changes (leg ulcers, hyperpigmentation with chronic use)

L-Asparaginase (Pegaspargase)

• Mechanism: Depletes circulating asparagine (normal cells synthesize own asparagine; leukemic lymphoblasts cannot — they are auxotrophic for asparagine) → protein synthesis failure → cell death
• Uses: ALL (induction — particularly childhood ALL; part of augmented BFM regimens)
• Toxicities:
  • Hypersensitivity reactions (IgE-mediated; use pegylated form — pegaspargase — to reduce immunogenicity)
  • Pancreatitis (can be severe/fatal)
  • Coagulopathy (decreases fibrinogen, factors II, V, VII, IX, X, antithrombin III, protein C/S → thrombosis AND bleeding)
  • Hepatotoxicity
  • Hyperglycemia (decreased insulin synthesis)
  • No myelosuppression (selective for lymphoblasts)

Etoposide (VP-16)

• Semi-synthetic derivative of podophyllotoxin (from mayapple plant)
• Mechanism: Inhibits topoisomerase II → double-strand DNA breaks. CCS (G1-S phase).
• Uses: Testicular cancer (BEP), SCLC (cisplatin + etoposide), Hodgkin lymphoma (BEACOPP), AML (part of some regimens), lymphomas
• Toxicities: Myelosuppression, mucositis, nausea, alopecia
• Secondary AML: Long-term risk of therapy-related AML — characterized by 11q23 (MLL gene) translocations, earlier onset (2–3 years after therapy) than alkylating agent-related AML

Tretinoin (ATRA — All-Trans Retinoic Acid)

• Mechanism: Binds retinoic acid receptor (RAR) → promotes differentiation of malignant promyelocytes into mature granulocytes (overcomes the PML-RARα fusion protein block)
• Uses: APL (Acute Promyelocytic Leukemia, AML-M3) — combined with arsenic trioxide (ATO) is now standard curative therapy
• ATRA syndrome (differentiation syndrome): Fever, pulmonary infiltrates, pleural/pericardial effusions, hypotension, renal failure — caused by cytokine release from differentiating promyelocytes → treat immediately with dexamethasone
• Also used: Acne (topical), psoriasis, head/neck cancer prevention

Arsenic Trioxide (ATO)

• APL: Induces differentiation and apoptosis of promyelocytes; combined with ATRA for highly curative APL therapy
• Toxicity: QT prolongation (risk of torsades de pointes — monitor ECG, correct electrolytes)

Bortezomib

• Mechanism: Proteasome inhibitor (26S proteasome) → prevents ubiquitin-proteasome degradation of pro-apoptotic proteins → accumulation of pro-apoptotic factors → cell death
• Uses: Multiple myeloma (VRd: Bortezomib + Revlimid/lenalidomide + dexamethasone), mantle cell lymphoma
• Toxicity: Peripheral neuropathy (dose-limiting; predominantly sensory), thrombocytopenia, herpes zoster reactivation (give prophylactic acyclovir)

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20. BCR-ABL TYROSINE KINASE INHIBITORS (TKIs)

Context

Mechanism

• Point mutations in BCR-ABL kinase domain (>100 mutations identified; T315I is most resistant)
• BCR-ABL gene amplification
• Activation of alternative signaling pathways

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21. GROWTH FACTOR RECEPTOR INHIBITORS

Epidermal Growth Factor Receptor (EGFR / HER1 / ErbB1)

Small-molecule EGFR TKIs (bind intracellular ATP-binding domain)

Anti-EGFR Monoclonal Antibodies (bind extracellular domain, block ligand binding)

HER2 (ErbB2) Inhibitors

VEGF/VEGFR Inhibitors

BRAF/MEK Inhibitors (relevant to melanoma/NSCLC)

• BRAF V600E mutation present in ~50% of melanomas, ~8% NSCLC, ~10% colorectal cancer (though colorectal BRAF-mutant tumors are resistant to BRAF inhibitors as monotherapy due to feedback EGFR activation)
• Vemurafenib, Dabrafenib: BRAF V600E inhibitors — used in BRAF-mutant melanoma and NSCLC
• Combined with MEK inhibitors (trametinib, cobimetinib) to prevent resistance from MAPK pathway reactivation
• Toxicities: Cutaneous squamous cell carcinoma (paradoxical MAPK activation in normal cells), photosensitivity, QT prolongation, fever (dabrafenib)

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KEY REGIMEN MNEMONICS (USMLE Favorites)

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TOXICITY QUICK-REFERENCE TABLE

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