How chemotherapy is tested on Step 1
Questions name a drug and ask for its mechanism, cell-cycle phase, or toxicity, or describe a toxicity and ask which drug caused it and what would have prevented it.
Chemotherapy cannot tell cancer from any rapidly dividing normal tissue — bone marrow, gut mucosa, hair follicles, and gonads. Drug-specific toxicities come from where each drug accumulates or how it is metabolized.
The cell cycle map
Cell-cycle-specific drugs act in one phase and are most effective against tumors with a high growth fraction; nonspecific drugs damage DNA in any phase.
Mechanism classes
Each class attacks DNA or its replication machinery differently.
| Drug | Mechanism | Signature toxicity | Prevention or antidote |
|---|---|---|---|
| Methotrexate | Inhibits dihydrofolate reductase | Myelosuppression, mucositis, hepatotoxicity, pulmonary fibrosis | Leucovorin rescue |
| 5-Fluorouracil | Inhibits thymidylate synthase | Myelosuppression, hand-foot syndrome | Uridine triacetate (overdose) |
| 6-Mercaptopurine | Blocks purine synthesis | Myelosuppression; toxic with allopurinol (xanthine oxidase) | Reduce dose with allopurinol; check TPMT |
| Cyclophosphamide | Alkylates DNA (activated by liver) | Hemorrhagic cystitis (acrolein), myelosuppression, bladder cancer | Mesna, hydration |
| Cisplatin, carboplatin | Cross-link DNA | Nephrotoxicity, ototoxicity, neuropathy, emesis | Hydration, amifostine |
| Doxorubicin | Intercalates; free radicals; topo II | Dilated cardiomyopathy (dose-dependent) | Dexrazoxane; cumulative dose limit |
| Bleomycin | Free radicals break DNA | Pulmonary fibrosis, skin changes | Limit dose; avoid high FiO₂ |
| Vincristine | Blocks microtubule polymerization | Peripheral neuropathy, constipation (ileus) | Dose limit |
| Vinblastine | Blocks microtubule polymerization | Myelosuppression | — |
| Paclitaxel | Stabilizes microtubules | Myelosuppression, neuropathy, hypersensitivity | Premedication |
| Busulfan | Alkylates DNA | Pulmonary fibrosis, hyperpigmentation | — |
Vincristine "spares" the marrow; vinblastine "blasts" it.
Toxicity by organ
Grouping toxicities by organ makes "which drug caused this?" questions faster.
Tumor lysis syndrome and clinical application
Rapid killing of large or fast-growing tumors (leukemias, Burkitt lymphoma) releases cell contents.
| Finding | Cause | Consequence |
|---|---|---|
| ↑ Potassium | Released from cells | Arrhythmias |
| ↑ Phosphate | Released from cells | Binds calcium → hypocalcemia, calcium phosphate in kidneys |
| ↑ Uric acid | Nucleic acid breakdown | Uric acid nephropathy → AKI |
| ↓ Calcium | Precipitates with phosphate | Tetany, seizures |
Prevention: aggressive IV hydration plus allopurinol (blocks uric acid formation) or rasburicase (breaks down uric acid).
A woman treated for breast cancer with an anthracycline-containing regimen develops dyspnea, orthopnea, and an S3 a year later. Echocardiogram shows a dilated left ventricle with EF 30%. Which drug is responsible and how could it have been prevented?
- Dilated cardiomyopathy after breast cancer chemotherapy suggests doxorubicin.
- Doxorubicin generates free radicals; cardiomyocytes have little catalase to neutralize them.
- Damage is cumulative and dose-dependent and is usually irreversible.
Answer. Doxorubicin. Prevention: limit cumulative dose, monitor EF, and use dexrazoxane (an iron chelator that reduces free radical formation).