STEPTRACKERPHARMACOLOGY + ONCOLOGY | ONCOLOGY | HIGH-YIELD REVIEW

Cytotoxic Chemotherapy

Classic chemotherapy kills dividing cells by attacking DNA synthesis, DNA itself or the mitotic spindle — and each drug has a signature organ toxicity and often a rescue or protective agent.

FOCUS ON

Antimetabolites (S phase): methotrexate (DHFR; myelosuppression reversed by leucovorin, mucositis, hepatotoxicity, pneumonitis), 5-FU (thymidylate synthase; leucovorin enhances; hand-foot syndrome, coronary vasospasm; DPD deficiency; overdose → uridine triacetate), capecitabine, 6-MP/azathioprine (purine synthesis; TPMT; ↑ with allopurinol), cytarabine (cerebellar toxicity), gemcitabine, hydroxyurea, fludarabine/cladribine. Alkylating agents: cyclophosphamide (hemorrhagic cystitis → mesna, hydration; SIADH), ifosfamide (+ Fanconi, encephalopathy), nitrosoureas (carmustine — CNS, pulmonary fibrosis), busulfan (pulmonary fibrosis, hyperpigmentation), cisplatin/carboplatin/oxaliplatin (cross-link; nephrotoxicity → amifostine, chloride diuresis; ototoxicity, neuropathy; oxaliplatin cold-induced). Antitumor antibiotics: doxorubicin/daunorubicin (dilated cardiomyopathy → dexrazoxane), bleomycin (pulmonary fibrosis, skin), dactinomycin. Microtubule (M phase): vincristine (neuropathy, constipation), vinblastine (marrow), paclitaxel/docetaxel (neuropathy, hypersensitivity). Topoisomerase: irinotecan/topotecan (topo I; diarrhea), etoposide (topo II; secondary AML).

DRUG

MECHANISM · PHASE

KEY USES

SIGNATURE TOXICITY · RESCUE

Methotrexate

DHFR inhibitor · S phase

ALL, choriocarcinoma, osteosarcoma, RA, psoriasis, ectopic pregnancy

Marrow, mucositis, hepatotoxicity, pneumonitis, renal (high dose) · leucovorin, glucarpidase

5-Fluorouracil · capecitabine

Thymidylate synthase inhibition (5-FdUMP) · S

Colorectal, GI, breast, head and neck; topical for actinic keratosis

Myelosuppression, mucositis, hand-foot syndrome, vasospasm · uridine triacetate

6-Mercaptopurine · azathioprine · 6-thioguanine

Purine analogs (HGPRT activation) · S

ALL maintenance, IBD, transplant

Marrow (TPMT/NUDT15 deficiency), hepatotoxicity, pancreatitis; ↓ dose with allopurinol

Cytarabine · gemcitabine · fludarabine · cladribine

Nucleoside analogs → DNA polymerase block · S

AML (cytarabine), pancreatic (gemcitabine), CLL, hairy cell leukemia (cladribine)

Cytarabine cerebellar ataxia, conjunctivitis; fludarabine autoimmune hemolysis

Cyclophosphamide · ifosfamide

Nitrogen mustards → DNA cross-links (prodrug, liver) · cell-cycle nonspecific

Lymphoma, breast, sarcoma, lupus nephritis, vasculitis

Hemorrhagic cystitis (acrolein) → mesna; bladder cancer, SIADH, infertility

Carmustine · lomustine · busulfan

Alkylators; nitrosoureas cross BBB

Brain tumors · CML, transplant conditioning

Pulmonary fibrosis, CNS toxicity · busulfan hyperpigmentation, seizures

Cisplatin · carboplatin · oxaliplatin

Platinum DNA cross-links

Testicular, ovarian, lung, bladder, head and neck, colorectal (oxaliplatin)

Nephrotoxicity, ↓ Mg²⁺, ototoxicity, neuropathy, emesis · amifostine, saline; carboplatin → marrow

Doxorubicin · daunorubicin

Intercalation, topo II block, free radicals

Breast, lymphoma, sarcoma, leukemia

Dose-dependent dilated cardiomyopathy → dexrazoxane; red urine, alopecia, extravasation necrosis

Bleomycin

Free radicals → DNA strand breaks · G2

Testicular cancer, Hodgkin lymphoma

Pulmonary fibrosis, skin hyperpigmentation, flagellate rash; little marrow toxicity

Vincristine · vinblastine

Bind tubulin → block polymerization · M

Lymphomas, ALL, Wilms, Hodgkin

Vincristine: neuropathy, constipation/ileus, SIADH · vinblastine: marrow; intrathecal = fatal

Paclitaxel · docetaxel

Stabilize microtubules (prevent breakdown) · M

Breast, ovarian, lung, prostate

Neuropathy, hypersensitivity (premedicate), myelosuppression, alopecia

Irinotecan · topotecan

Topoisomerase I inhibitors · S

Colorectal (irinotecan), ovarian, small cell lung

Severe diarrhea (irinotecan: UGT1A1*28), myelosuppression

Etoposide · teniposide

Topoisomerase II inhibitors · late S–G2

Testicular, small cell lung, leukemia

Myelosuppression, secondary AML (11q23), alopecia

Picture it — where chemotherapy acts in the cell cycle

Cell-cycle specificityAntimetabolites and topoisomerase I inhibitors act in S phase; bleomycin and etoposide in G2; vinca alkaloids and taxanes in M phase; CDK4/6 inhibitors hold cells in G1. Alkylators, platinum compounds and anthracyclines damage DNA in any phase, including resting cells.

Schematic diagrams, not to scale.

Mechanism — tumor lysis syndrome

Bulky, fast tumor treatedBurkitt, ALL, AML

→

Cells burst↑ K⁺, ↑ PO₄³⁻, ↑ uric acid, ↓ Ca²⁺

→

AKI, arrhythmia, seizures

→

Prevent: IV fluids, allopurinol or rasburicase

Toxicity → protective agent

DRUG

TOXICITY

PROTECTOR

Cyclophosphamide

Hemorrhagic cystitis

Mesna

Doxorubicin

Cardiomyopathy

Dexrazoxane

Cisplatin

Nephrotoxicity

Amifostine, saline

Methotrexate

Marrow, mucositis

Leucovorin

5-FU

Overdose

Uridine triacetate

How it's tested

COMMON CONFUSIONLeucovorin rescues normal cells from methotrexate but potentiates 5-FU (stabilizes its binding to thymidylate synthase).

THE TRAPBleomycin and busulfan cause lung fibrosis; high oxygen during later surgery worsens bleomycin lung injury — tell the anesthesiologist.

YOUR APPROACHCancer → regimen drug → mechanism/phase → signature toxicity → monitoring and protective agent.

If you see… think…

Hematuria after chemotherapy for lymphoma → cyclophosphamide (acrolein) → mesna

Heart failure years after breast cancer chemo → doxorubicin

Dry cough and restrictive PFTs after testicular cancer therapy → bleomycin

Hearing loss and low Mg²⁺ → cisplatin

Foot drop and constipation on leukemia therapy → vincristine

Severe diarrhea, Gilbert variant → irinotecan

Secondary AML with 11q23 rearrangement → etoposide

Cold-induced throat and finger paresthesias → oxaliplatin

Pancytopenia on 6-MP after starting allopurinol → xanthine oxidase inhibition

Microtubule stabilizer → paclitaxel