Anticancer drugs have evolved from non-selective cytotoxic agents that kill rapidly dividing cells to targeted therapies that exploit specific molecular vulnerabilities of cancer cells and immunotherapies that unleash the immune system against tumors.
Cytotoxic Chemotherapy
Cytotoxic chemotherapy kills rapidly dividing cells by interfering with DNA synthesis, replication, or cell division. It has a narrow therapeutic index and affects all rapidly dividing tissues (bone marrow, GI tract, hair follicles, reproductive organs).
Alkylating Agents
Alkylating agents add alkyl groups to DNA bases, causing cross-linking and strand breaks. Cyclophosphamide is used for lymphomas, breast cancer, ovarian cancer, and as an immunosuppressant. Ifosfamide is similar but more bladder-toxic. Both require adequate hydration and mesna (a uroprotectant) to prevent hemorrhagic cystitis. Busulfan is used in conditioning regimens for bone marrow transplantation. Nitrosoureas (carmustine, lomustine) cross the blood-brain barrier and are used for brain tumors. Side effects of alkylating agents include myelosuppression (dose-limiting), nausea/vomiting, alopecia, hemorrhagic cystitis (cyclophosphamide, ifosfamide), and secondary malignancies (AML — risk increases with cumulative dose).
Antimetabolites
Antimetabolites interfere with DNA and RNA synthesis by mimicking normal metabolites. Methotrexate inhibits dihydrofolate reductase, blocking folate metabolism needed for nucleotide synthesis. It is used for leukemia, lymphoma, breast cancer, and as an immunosuppressant for rheumatoid arthritis. Leucovorin (folinic acid) is used as rescue therapy. 5-fluorouracil (5-FU) inhibits thymidylate synthase needed for DNA synthesis — used for colorectal, breast, and head and neck cancers. Capecitabine is an oral prodrug of 5-FU. Capecitabine causes hand-foot syndrome (palmar-plantar erythrodysesthesia). Capecitabine and 5-FU are contraindicated in patients with DPD (dihydropyrimidine dehydrogenase) deficiency (3-5% of the population). Cytarabine is used for acute leukemias. Gemcitabine is used for pancreatic, lung, and bladder cancers. Mercaptopurine and thioguanine are used for leukemias.
Plant Alkaloids
Vinca alkaloids (vincristine, vinblastine) bind to tubulin, inhibiting microtubule formation and mitotic spindle function. Vincristine is used for leukemias and lymphomas — its dose-limiting toxicity is peripheral neuropathy (cumulative). Vinblastine causes more myelosuppression. Taxanes (paclitaxel, docetaxel) stabilize microtubules, preventing their disassembly during mitosis. They are used for breast, ovarian, lung, and prostate cancers. Taxanes require premedication for hypersensitivity reactions. Docetaxel causes fluid retention. Paclitaxel causes peripheral neuropathy. Nab-paclitaxel is albumin-bound and reduces hypersensitivity risk.
Platinum Agents
Cisplatin, carboplatin, and oxaliplatin form DNA cross-links, triggering apoptosis. Cisplatin is used for testicular, ovarian, head and neck, and lung cancers. Dose-limiting toxicity: nephrotoxicity (requires aggressive hydration and magnesium supplementation), ototoxicity (tinnitus, high-frequency hearing loss), and peripheral neuropathy. Carboplatin is less nephrotoxic and ototoxic but causes more myelosuppression. Its dosing is based on renal function (Calvert formula). Oxaliplatin causes acute cold-triggered dysesthesias and chronic peripheral neuropathy. It is used primarily for colorectal cancer.
Targeted Therapy
Targeted therapies exploit specific molecular alterations in cancer cells — driver mutations, amplified oncogenes, and aberrant signaling pathways. They are cytostatic rather than cytotoxic in many cases and have a better therapeutic index than conventional chemotherapy.
Tyrosine Kinase Inhibitors
TKIs target kinases involved in cancer cell growth and survival. Imatinib targets BCR-ABL in chronic myeloid leukemia — it revolutionized CML treatment (10-year survival over 85%). Erlotinib and gefitinib target EGFR in non-small cell lung cancer with EGFR mutations. Osimertinib is a third-generation EGFR TKI effective against the T790M resistance mutation and CNS metastases. Sunitinib and sorafenib target VEGFR and other kinases in renal cell carcinoma and hepatocellular carcinoma. Lenvatinib is used for thyroid cancer and HCC. TKIs are oral medications with side effects including fatigue, diarrhea, skin rash, hand-foot syndrome, hypertension (anti-VEGFR drugs), hypothyroidism, and hepatotoxicity.
Monoclonal Antibodies
Trastuzumab (Herceptin) targets HER2 in HER2-positive breast and gastric cancers. It can cause cardiotoxicity (left ventricular dysfunction — requires serial echocardiograms). Rituximab targets CD20 on B-cells — used for lymphomas and autoimmune diseases. Infusion reactions are common. Bevacizumab targets VEGF, inhibiting angiogenesis — used for colorectal, lung, and other cancers. It causes hypertension, bleeding, and impaired wound healing. Cetuximab and panitumumab target EGFR in colorectal and head and neck cancers. Immune checkpoint inhibitors (pembrolizumab, nivolumab, atezolizumab, ipilimumab) are antibodies that block immune checkpoints (PD-1, PD-L1, CTLA-4), releasing the immune system’s brakes to attack cancer cells.
Immune Checkpoint Inhibitors
Pembrolizumab and nivolumab (anti-PD-1) are approved for multiple cancers: melanoma, non-small cell lung cancer, head and neck, bladder, kidney, Hodgkin lymphoma, and any MSI-high or TMB-high solid tumor. Ipilimumab (anti-CTLA-4) is used for melanoma. Checkpoint inhibitors cause immune-related adverse events (irAEs) — potentially any organ: dermatitis (rash, pruritus — most common, 30-40%), colitis (diarrhea, can be severe — 10-20% with ipilimumab), hepatitis, pneumonitis (especially in lung cancer patients, 3-5%), endocrinopathies (thyroiditis, hypophysitis, adrenal insufficiency, type 1 diabetes — 10-20%), and less commonly myocarditis, nephritis, and neurologic toxicity. Most irAEs are managed with corticosteroids and holding immunotherapy.
PARP Inhibitors
Olaparib, rucaparib, niraparib, and talazoparib inhibit poly(ADP-ribose) polymerase, an enzyme involved in DNA repair. They exploit synthetic lethality in tumors with BRCA1/2 mutations (breast, ovarian, pancreatic, prostate cancers). Side effects include fatigue, nausea, myelosuppression, and increased risk of myelodysplastic syndrome/AML.
Hormonal Therapy
Hormonal therapies are used for hormone receptor-positive breast and prostate cancers. Tamoxifen (SERM) blocks estrogen receptors in breast tissue. Aromatase inhibitors (letrozole, anastrozole, exemestane) reduce estrogen production in postmenopausal women. Fulvestrant degrades the estrogen receptor. Anti-androgens (enzalutamide, apalutamide, darolutamide) block androgen receptors in prostate cancer. GnRH agonists (leuprolide, goserelin) suppress testosterone production. Abiraterone inhibits CYP17, reducing androgen synthesis.
Summary
Cytotoxic chemotherapy targets rapidly dividing cells through DNA damage and mitotic disruption, with dose-limiting myelosuppression, GI toxicity, and alopecia. Targeted therapy exploits specific molecular vulnerabilities (TKIs, monoclonal antibodies). Immunotherapy (checkpoint inhibitors) produces durable responses in a subset of patients with distinct immune-related adverse events. Hormonal therapy targets steroid receptors in breast and prostate cancers. The treatment landscape continues to evolve with combination strategies, biomarker-driven patient selection, and novel modalities (bispecific T-cell engagers, antibody-drug conjugates, CAR-T cells).