Chemotherapy & Hematology Pharmacology

Cell-Cycle Principles and Antimetabolites

Cell-cycle specificity. Phase-specific drugs act on cycling cells: antimetabolites in S phase, bleomycin in G2, topoisomerase inhibitors in S and G2, and microtubule drugs in M phase. Alkylating agents, platinum compounds, and anthracyclines damage DNA in any phase (cell-cycle NONspecific). Rapidly dividing normal tissues explain the shared toxicities of myelosuppression, mucositis, and alopecia.

Methotrexate. Inhibits dihydrofolate reductase (DHFR), blocking tetrahydrofolate regeneration and thus dTMP and purine synthesis (S-phase specific). Leucovorin (folinic acid) is already reduced, so it bypasses the block and rescues normal cells. Methotrexate is also used for rheumatoid arthritis, ectopic pregnancy, and abortion. Toxicities: myelosuppression, hepatotoxicity, pulmonary fibrosis, and mucositis; it is teratogenic.

5-Fluorouracil (5-FU). A pyrimidine analog converted to 5-F-dUMP, which inhibits thymidylate synthase (a folate-requiring enzyme) and blocks dTMP synthesis (S phase). Leucovorin POTENTIATES 5-FU by stabilizing the drug–enzyme–folate complex, which also worsens toxicity. Toxicities: myelosuppression, severe with dihydropyrimidine dehydrogenase (DPD) deficiency because the drug cannot be broken down, and hand-foot syndrome. It is used in colorectal and other solid tumors.

Leucovorin RESCUES methotrexate toxicity but POTENTIATES 5-FU.

6-Mercaptopurine (6-MP). 6-MP (and azathioprine, its prodrug) is activated by HGPRT and blocks de novo purine synthesis. It is metabolized by xanthine oxidase, so allopurinol or febuxostat raises 6-MP levels and toxicity; reduce the 6-MP dose. Toxicities are myelosuppression and hepatotoxicity, and thiopurine methyltransferase (TPMT) deficiency increases the risk.

Hydroxyurea. Inhibits ribonucleotide reductase (S phase); it is used in CML, polycythemia vera, and sickle cell disease, where it raises fetal hemoglobin.

DNA-Damaging Agents

Cyclophosphamide. A prodrug activated by hepatic cytochrome P450 that crosslinks DNA at guanine N-7 (cell-cycle NONspecific). Its metabolite ACROLEIN causes hemorrhagic cystitis, prevented with MESNA, which binds acrolein in the bladder, plus aggressive hydration. It can also cause SIADH. Ifosfamide shares the acrolein toxicity and adds neurotoxicity.

Platinum compounds. Cisplatin and carboplatin crosslink DNA (cell-cycle nonspecific) and are used in testicular, ovarian, lung, and bladder cancers. Signature toxicities are NEPHROTOXICITY, prevented with saline diuresis and amifostine (a free-radical scavenger), ototoxicity, and peripheral neuropathy; carboplatin is less nephrotoxic but more myelosuppressive.

Anthracyclines. Doxorubicin and daunorubicin intercalate into DNA, generate free radicals, and inhibit topoisomerase II; they are used broadly across solid and hematologic malignancies. The signature toxicity is cumulative, dose-dependent DILATED cardiomyopathy from free-radical injury to cardiomyocytes. DEXRAZOXANE chelates iron and limits this free-radical cardiotoxicity.

Bleomycin and busulfan. Bleomycin generates free radicals that cause DNA strand breaks (G2 phase); it causes PULMONARY FIBROSIS and skin hyperpigmentation but minimal myelosuppression. Busulfan, an alkylator, also causes pulmonary fibrosis plus hyperpigmentation and is used to ablate the marrow before stem-cell transplant.

Topoisomerase and Microtubule Inhibitors

Topoisomerase inhibitors. Etoposide and teniposide inhibit topoisomerase II, increasing DNA strand breaks (S and G2 phases). Irinotecan and topotecan inhibit topoisomerase I. All cause myelosuppression; irinotecan also causes severe diarrhea, early (cholinergic) and late (secretory), and its active metabolite is cleared by UGT1A1, so reduced UGT1A1 activity increases toxicity.

Vinca alkaloids. Vincristine and vinblastine bind β-tubulin and block microtubule ASSEMBLY, arresting cells in M phase. VinCRIStine is neurotoxic (peripheral neuropathy, areflexia, constipation or paralytic ileus); vinBLASTine Blasts the Bone marrow.

Taxanes. Paclitaxel HYPERstabilizes polymerized microtubules so the spindle cannot break down (M phase), causing neuropathy and myelosuppression.

Targeted Agents

Imatinib. A tyrosine kinase inhibitor that blocks the BCR-ABL kinase of CML and c-KIT in gastrointestinal stromal tumor (GIST).

Rituximab. An anti-CD20 monoclonal antibody used for B-cell lymphomas, ITP, and rheumatoid arthritis. Depleting B cells can reactivate hepatitis B and allow progressive multifocal leukoencephalopathy (PML) from JC virus, so patients are screened for hepatitis B first.

Trastuzumab. An anti-HER2 antibody for HER2-positive breast cancer. It causes CARDIOTOXICITY that is usually reversible, unlike the dose-dependent, irreversible cardiomyopathy of anthracyclines.

Anticoagulants and Thrombolytics

Heparin. Unfractionated heparin activates antithrombin, which then inhibits thrombin (IIa) and factor Xa. It is given IV with immediate onset, monitored by the PTT, reversed by protamine, and safe in pregnancy because it does not cross the placenta, but it risks heparin-induced thrombocytopenia (HIT). Low-molecular-weight heparin (enoxaparin) inhibits factor Xa more than IIa and needs no routine monitoring.

Warfarin. Inhibits vitamin K epoxide reductase, so factors II, VII, IX, and X and proteins C and S are made without γ-carboxylation. It is oral, has a delayed onset, is monitored by PT/INR, is reversed by vitamin K plus FFP or prothrombin complex concentrate (PCC), and is teratogenic. Protein C falls before factors II, IX, and X, causing a transient hypercoagulable state (and warfarin skin necrosis), so therapy is bridged with heparin.

Direct oral anticoagulants (DOACs). Dabigatran is a direct thrombin (IIa) inhibitor reversed by IDARUCIZUMAB. Rivaroxaban and apixaban are direct factor Xa inhibitors reversed by ANDEXANET ALFA (withdrawn from the US market in December 2025; four-factor PCC is used instead). None needs routine monitoring.

Thrombolytics. Alteplase (tPA), reteplase, and streptokinase convert plasminogen to plasmin, which cleaves fibrin and dissolves formed clots in acute ischemic stroke, acute MI, and massive PE. The major toxicity is bleeding, reversed with the antifibrinolytics aminocaproic acid or tranexamic acid plus cryoprecipitate or FFP. They are contraindicated with active bleeding, recent surgery, or a prior hemorrhagic stroke.