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Anticancer Drugs - Pharmacology Notes

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I. OVERVIEW

• Defective normal control mechanisms of cell survival, proliferation, and differentiation
• Expression of abnormal cell surface antigens
• Chromosomal abnormalities (translocations, fusions, gene amplification)
• Tumor stem cells with clonogenic capability and metastatic potential
• Genetic instability leading to drug resistance

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II. CELL CYCLE CONCEPTS

Cell Cycle Phases

Cell Cycle-Specific (CCS) Agents - act only in specific phases:

• S phase: Antimetabolites (MTX, 5-FU, cytarabine, gemcitabine, 6-MP)
• G1-S phase: Etoposide (Topoisomerase II inhibitor)
• G2-M phase: Camptothecins (topoisomerase I inhibitors), bleomycin
• M phase: Taxanes (paclitaxel, docetaxel), Vinca alkaloids (vincristine, vinblastine)

Cell Cycle-Nonspecific (CCNS) Agents - effective in any phase:

• Alkylating agents, nitrosoureas, platinum compounds
• Anthracyclines (doxorubicin, daunorubicin)
• Dacarbazine, temozolomide

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III. ANTIMETABOLITES

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A. Folate Antagonists

Methotrexate (MTX)

• MOA: Inhibits dihydrofolate reductase (DHFR) → depletes tetrahydrofolate (THF) → blocks thymidylate and purine synthesis → inhibits DNA/RNA synthesis
• Routes: IV, PO, IM, intrathecal (IT)
• Uses: ALL, choriocarcinoma, breast cancer, non-Hodgkin lymphoma, osteosarcoma
• Toxicity: Myelosuppression, mucositis/stomatitis, N/V/D, rash, alopecia; high-dose → renal damage; IT → neurologic toxicities
• Rescue: Leucovorin (folinic acid) - can prevent/reverse toxicity
• Drug interactions: NSAIDs, penicillins, cephalosporins (reduce renal excretion → increase toxicity); omeprazole, warfarin
• Note: Dose-adjust in renal impairment

Pemetrexed (ALIMTA)

• MOA: Multi-targeted antifolate - inhibits DHFR, thymidylate synthase, and GARFT
• Uses: Non-small cell lung cancer, mesothelioma
• Note: Folic acid and B12 supplementation required to reduce toxicity

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B. Pyrimidine Analogs

5-Fluorouracil (5-FU)

• MOA: Converted to FdUMP → inhibits thymidylate synthase → blocks dTMP synthesis → "thymineless death." Also incorporated into RNA as FUTP
• Route: IV (oral bioavailability poor)
• Uses: Colorectal, breast, head & neck, gastric cancers
• Toxicity:
  • Bolus dosing: myelosuppression
  • Continuous infusion: hand-foot syndrome (palmar-plantar erythrodysesthesia - erythematous desquamation of palms/soles), mucositis
  • Coronary vasospasm
• Leucovorin stabilizes FdUMP-TS complex → enhances 5-FU activity (used in FOLFOX, FOLFIRI regimens)

Capecitabine (XELODA)

• MOA: Oral prodrug of 5-FU; converted to 5-FU preferentially in tumor tissue
• Route: PO (taken within 30 min of a meal)
• Uses: Colorectal, breast cancers
• Toxicity: Diarrhea, mucositis, myelosuppression, hand-foot syndrome, chest pain
• Drug interactions: Warfarin, phenytoin

Cytarabine (Ara-C)

• MOA: Converted by deoxycytidine kinase to ara-CTP → competitively inhibits DNA polymerase-α and DNA polymerase-β → blocks DNA synthesis and repair; also incorporated into DNA causing chain termination
• Routes: IV, IT
• Uses: AML, non-Hodgkin lymphoma (hematologic malignancies ONLY - no activity in solid tumors)
• Toxicity: Myelosuppression, mucositis, N/V, neurotoxicity (high dose)
• Note: Short half-life; usually given by continuous infusion x 5-7 days

Gemcitabine (INFUGEM)

• MOA: Fluorinated deoxycytidine analog. Metabolized to di- and triphosphate forms:
  • Diphosphate inhibits ribonucleotide reductase → reduces dNTP pool
  • Triphosphate inhibits DNA polymerases → blocks synthesis/repair
  • Incorporated into DNA → inhibition of synthesis
• Uses: Pancreatic, lung, bladder, ovarian, breast cancers

Azacitidine (VIDAZA)

• MOA: DNA hypomethylating agent; at low doses, inhibits DNA methyltransferase → reactivates silenced tumor suppressor genes
• Uses: Myelodysplastic syndromes (MDS), AML

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C. Purine Analogs

6-Mercaptopurine (6-MP)

• MOA: Converted by HGPRT to 6-TIMP → inhibits purine ring biosynthesis and interconversion; incorporated into DNA/RNA
• Route: PO
• Uses: ALL (maintenance)
• Toxicity: Myelosuppression, hepatotoxicity (jaundice), N/V/D
• Critical interaction: Allopurinol inhibits xanthine oxidase (which metabolizes 6-MP) → reduce 6-MP dose by 50-75% when co-administered

Fludarabine

• MOA: Fluorinated purine analog; converted to triphosphate → inhibits DNA polymerase and ribonucleotide reductase; causes DNA strand breaks
• Route: IV
• Uses: CLL, low-grade lymphomas
• Toxicity: Myelosuppression, profound immunosuppression (↑ risk of opportunistic infections), N/V/D, neurologic toxicity, fever, edema
• Note: Adjust dose in renal impairment

Cladribine

• MOA: Chlorinated purine analog; resistant to adenosine deaminase; selectively toxic to lymphocytes
• Route: IV/SC
• Uses: Hairy cell leukemia, CLL
• Toxicity: Neutropenia, immunosuppression, fever, N/V, teratogenic, peripheral neuropathy

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IV. ALKYLATING AGENTS

• DNA interstrand and intrastrand cross-links (most important)
• Abnormal base pairing (guanine:thymine instead of guanine:cytosine)
• Depurination (excision of guanine) → strand breaks

• Increased DNA repair enzyme activity
• Decreased drug transport into cell
• Increased glutathione conjugation (glutathione S-transferase)

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A. Nitrogen Mustards

Cyclophosphamide

• Special: Inactive prodrug; activated in liver by CYP450 to 4-hydroxycyclophosphamide ⇌ aldophosphamide → nonenzymatic cleavage to phosphoramide mustard (cytotoxic) + acrolein
• Acrolein → hemorrhagic cystitis (prevented by MESNA and adequate hydration)
• Route: PO and IV (high oral bioavailability - unique advantage)
• Uses: Breast cancer, lymphomas, leukemias, myeloma, sarcomas; also immunosuppression
• Toxicities: Myelosuppression, hemorrhagic cystitis, alopecia, SIADH (at high doses), N/V; at high doses → cardiotoxicity

Ifosfamide

• MOA: Similar to cyclophosphamide (requires hepatic activation)
• Also produces acrolein → hemorrhagic cystitis (always give with MESNA)
• Toxicity: Also causes CNS toxicity (encephalopathy, confusion)

Chlorambucil (LEUKERAN)

• Uses: CLL, low-grade lymphomas

Melphalan

• Uses: Multiple myeloma, ovarian cancer

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B. Nitrosoureas

Carmustine (BCNU), Lomustine (CCNU)

• Key property: Lipid-soluble → cross blood-brain barrier → used for brain tumors (glioblastoma)
• MOA: Alkylation + carbamoylation of lysine residues of proteins (via isocyanates) - dual mechanism
• Toxicity: Delayed and prolonged myelosuppression (nadir at 4-6 weeks), pulmonary fibrosis (carmustine), N/V
• BCNU (carmustine) also available as GLIADEL wafer - implanted in brain tumor resection cavity

Streptozocin

• Uses: Pancreatic islet cell tumors
• Toxicity: Nephrotoxicity (dose-limiting), minimal myelosuppression

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C. Triazenes / Methylating Agents

Dacarbazine (DTIC)

• MOA: Prodrug; metabolized to methyldiazonium ion → methylates DNA at O6 and N7 of guanine
• Route: IV
• Uses: Malignant melanoma, Hodgkin lymphoma (ABVD regimen)

Temozolomide (TEMODAR)

• MOA: Similar to dacarbazine but spontaneously activated (no hepatic activation needed); methylates DNA at O6 and N7 of guanine
• Route: PO (oral bioavailability ~100%)
• Uses: Glioblastoma multiforme, anaplastic astrocytoma, melanoma

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D. Platinum Coordination Complexes

Cisplatin

• MOA: In plasma (high Cl⁻ environment) - remains neutral; enters cell, loses chloride in low-Cl⁻ environment → binds to N7 of guanine → inter- and intrastrand cross-links → inhibits DNA polymerases and transcription
• Routes: IV, IP, IA
• Uses: Testicular (with vinblastine + bleomycin - curative!), ovarian, bladder, lung, head & neck cancers
• Toxicities: Nephrotoxicity (dose-limiting - requires aggressive hydration), ototoxicity (irreversible), peripheral neuropathy, severe N/V (highly emetogenic), electrolyte wasting (Mg²⁺, K⁺, Ca²⁺ loss), myelosuppression
• Note: Pre- and post-hydration mandatory; high incidence of N/V

Carboplatin

• MOA: Same as cisplatin (guanine cross-linking)
• Less nephrotoxic, ototoxic, and neurotoxic than cisplatin
• Dose-limiting toxicity: Myelosuppression (thrombocytopenia)
• Dose calculated using AUC (Calvert formula)
• Preferred when vigorous hydration not possible

Oxaliplatin

• Uses: Colorectal cancer (FOLFOX regimen with 5-FU + leucovorin)
• Unique toxicity: Cold-related and cumulative peripheral neuropathy (touching cold objects causes acute dysesthesias)
• Also: hepatotoxicity

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V. NATURAL PRODUCTS

A. Vinca Alkaloids (M phase - CCS)

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B. Taxanes (M phase - CCS)

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C. Topoisomerase Inhibitors

Topoisomerase II Inhibitors (Epipodophyllotoxins)

Etoposide (VP-16)

• MOA: Inhibits topoisomerase II → prevents re-ligation of DNA strand breaks → accumulation of double-strand breaks → apoptosis
• Uses: Lung cancer (small cell), testicular cancer, lymphomas
• Toxicities: Myelosuppression, alopecia, N/V; secondary leukemia (AML)

Topoisomerase I Inhibitors (Camptothecins) - G2-M phase

Irinotecan (CPT-11)

• MOA: Prodrug; active metabolite SN-38 inhibits topoisomerase I → single-strand DNA breaks
• Uses: Colorectal cancer (FOLFIRI regimen), lung cancer
• Key toxicity: Severe diarrhea (two types: early - cholinergic, treat with atropine; late - treat with loperamide); myelosuppression
• Note: Patients with UGT1A1*28 polymorphism → reduced SN-38 glucuronidation → increased toxicity (increased diarrhea and neutropenia)

Topotecan

• Uses: Ovarian cancer, SCLC, cervical cancer
• Toxicities: Myelosuppression, N/V

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D. Antitumor Antibiotics

Anthracyclines

Doxorubicin (ADRIAMYCIN)

• MOA: Multiple mechanisms:
  1. Intercalation into DNA → inhibits DNA/RNA synthesis
  2. Inhibition of topoisomerase II → DNA strand breaks
  3. Formation of free radicals (reactive oxygen species) → lipid peroxidation → membrane damage
• Uses: Breast cancer, lymphomas, sarcomas, AML, ovarian, thyroid cancers (one of the broadest spectrum)
• Key toxicity: Cumulative cardiotoxicity (dilated cardiomyopathy) - dose-limiting when cumulative dose >550 mg/m² - related to free radical generation
  • Dexrazoxane (iron chelator) - cardioprotective (reduces free radical formation)
• Other toxicities: Myelosuppression, alopecia (complete), mucositis/stomatitis, N/V, red urine (drug is red - warn patient), vesicant
• DOXIL: Liposomal formulation - reduces cardiotoxicity; used in Kaposi's sarcoma, ovarian cancer

Daunorubicin

• Similar to doxorubicin
• Uses: AML, ALL

Epirubicin (ELLENCE)

• Uses: Breast cancer

Idarubicin

• Uses: AML

Mitoxantrone

• MOA: Anthracenedione (anthraquinone) - inhibits topoisomerase II; some intercalation; generates fewer free radicals than doxorubicin
• Uses: AML, prostate cancer, MS (reduces relapse)
• Less cardiotoxic than doxorubicin (but still cumulative cardiotoxicity)
• Urine/sclera may appear blue-green

Bleomycin (G2-M phase)

• MOA: Glycopeptide antibiotic. Binds to DNA + O₂ + Fe²⁺ → free radical formation → single- and double-strand DNA breaks. Acts in G2 and M phase
• Uses: Testicular cancer (BEP regimen: bleomycin + etoposide + cisplatin), Hodgkin lymphoma (ABVD), squamous cell carcinoma
• Key toxicity: Pulmonary fibrosis/pneumonitis (dose-limiting and potentially irreversible - accumulates in skin and lungs which lack bleomycin hydrolase)
• Other: Skin toxicity (pigmentation, thickening, "flagellate" hyperpigmentation), fever/chills
• Minimal myelosuppression (useful in this regard)
• Contraindicated pre-surgery with high FiO₂ (oxygen exacerbates pulmonary toxicity)

Dactinomycin (Actinomycin D)

• MOA: Intercalates between G-C base pairs in DNA → inhibits RNA polymerase → blocks transcription
• Uses: Wilms tumor, rhabdomyosarcoma, Ewing's sarcoma, gestational trophoblastic disease
• Toxicities: Myelosuppression, mucositis, N/V, alopecia, vesicant

Mitomycin C

• MOA: Alkylating agent (requires bioactivation by reductive enzymes) → cross-links DNA; also inhibits DNA synthesis
• Uses: Bladder cancer (intravesical), gastric, colorectal, cervical cancers
• Toxicity: Delayed myelosuppression, hemolytic uremic syndrome (HUS), pulmonary fibrosis

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VI. HORMONAL AGENTS

A. Estrogen Receptor Modulators / Antagonists

Tamoxifen (SOLTAMOX)

• MOA: Selective estrogen receptor modulator (SERM) - antagonist in breast tissue, partial agonist in bone/uterus
• Uses: Estrogen receptor-positive (ER+) breast cancer (adjuvant and metastatic); also prevention
• Metabolized by CYP2D6 to active metabolite endoxifen (important pharmacogenomics consideration)
• Toxicities: Hot flushes, vaginal bleeding/discharge, increased risk of endometrial cancer (uterine agonism), thromboembolism (DVT/PE), cataracts

Fulvestrant (FASLODEX)

• MOA: Pure estrogen receptor antagonist (selective estrogen receptor downregulator - SERD) - no agonist activity
• Uses: ER+ metastatic breast cancer after antiestrogen failure
• Route: IM injection

Raloxifene (EVISTA)

• MOA: SERM - antagonist in breast and uterus, agonist in bone
• Uses: Prevention of breast cancer; osteoporosis prevention
• No increased endometrial cancer risk (unlike tamoxifen)

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B. Aromatase Inhibitors (AIs)

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C. GnRH Agonists (Medical castration)

Leuprolide, Goserelin, Triptorelin

• MOA: Continuous administration → downregulation of GnRH receptors → desensitization of pituitary → paradoxical decrease in LH/FSH → decreased testosterone (in men) and estrogen (in women)
• Initial flare: First 1-2 weeks - transient increase in testosterone (tumor flare) - mitigate with antiandrogen
• Uses: Prostate cancer, breast cancer, endometriosis, uterine fibroids, precocious puberty
• Route: SC or IM depot injections (monthly or quarterly)

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D. Antiandrogens

Flutamide, Bicalutamide, Nilutamide, Darolutamide, Enzalutamide

• MOA: Competitive antagonists at androgen receptor
• Uses: Prostate cancer (usually combined with GnRH agonist = total androgen blockade)

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VII. TARGETED THERAPIES

A. Monoclonal Antibodies

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B. Kinase Inhibitors

BCR-ABL Inhibitors (Imatinib and relatives)

• Toxicities: N/V, edema, fluid retention, myelosuppression, hepatotoxicity
• Imatinib = paradigm-shift drug - first targeted therapy for CML (achieved >90% complete hematologic response)

EGFR Inhibitors

• Toxicities: Acneiform rash (correlates with efficacy!), diarrhea, ILD/pneumonitis

BRAF Inhibitors

• Toxicities: Paradoxical cutaneous squamous cell carcinoma, photosensitivity, arthralgias

MEK Inhibitor

• Trametinib (MEKINIST): BRAF V600E/K mutant melanoma (often combined with BRAF inhibitor)

ALK/ROS1 Inhibitor

• Crizotinib (XALKORI): ALK-rearranged or ROS1+ NSCLC
• Toxicities: Visual disturbances, N/V, hepatotoxicity, bradycardia

BTK Inhibitor

• Ibrutinib (IMBRUVICA): CLL, mantle cell lymphoma, Waldenström macroglobulinemia
• Toxicities: Bleeding, atrial fibrillation, diarrhea, infections

PI3K Inhibitor

• Idelalisib (ZYDELIG): CLL, follicular lymphoma
• Toxicities: Diarrhea/colitis, hepatotoxicity, pneumonitis, infections

JAK Inhibitor

• Ruxolitinib (JAKAVI): Myelofibrosis, polycythemia vera

Multikinase Inhibitors

• Sorafenib (NEXAVAR): Renal cell carcinoma, hepatocellular carcinoma, thyroid cancer - targets VEGFR, PDGFR, Raf kinases
• Toxicity: Hand-foot syndrome, hypertension, diarrhea

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VIII. IMMUNOTHERAPY / CHECKPOINT INHIBITORS

Mechanism

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IX. CAR-T CELL THERAPY (Cellular Gene Therapy)

• Cytokine Release Syndrome (CRS): Fever, hypotension, hypoxia - treat with tocilizumab (anti-IL-6)
• Neurotoxicity (ICANS): Confusion, aphasia, seizures

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X. KEY COMBINATION REGIMENS

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XI. COMMON/DISTINCTIVE TOXICITIES - HIGH-YIELD SUMMARY

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XII. DRUG-SPECIFIC ANTIDOTES / RESCUE AGENTS

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XIII. PHARMACOGENOMICS HIGHLIGHTS

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