DNA-Damaging Chemotherapy: Alkylators, Platinums & Antitumor Antibiotics

Overview: DNA as the target

Alkylating agents. These drugs form reactive electrophiles, many only after metabolic activation, that attach alkyl groups covalently to DNA bases, chiefly the N7 position of guanine. Bifunctional agents bond two bases, creating cross-links that prevent strand separation and stall replication and transcription, triggering apoptosis. Because the damage does not depend on cell-cycle phase, alkylators are cell-cycle nonspecific and also kill resting cells; bone marrow, gonads, and GI mucosa bear the toxicity. Tumors resist through enhanced DNA repair (such as the repair enzyme MGMT) or glutathione conjugation.

Related classes. Platinum compounds act like alkylators, forming mostly intrastrand cross-links between adjacent guanines. Antitumor antibiotics are Streptomyces products that damage DNA by free radicals (bleomycin) or intercalation (dactinomycin).

Cyclophosphamide and ifosfamide

Activation and uses. Both are nitrogen mustard prodrugs converted by hepatic CYP450 into phosphoramide mustard, the DNA cross-linker, and acrolein, a urotoxic by-product. Cyclophosphamide treats lymphomas (the C in CHOP), breast cancer, and leukemias and is a potent immunosuppressant for lupus nephritis and ANCA-associated vasculitis. Ifosfamide treats sarcomas and testicular cancer.

Hemorrhagic cystitis. Acrolein concentrates in urine and injures the urothelium, causing hematuria; chronic exposure raises bladder cancer risk. Prevention is vigorous hydration plus mesna, a thiol drug excreted into urine, where it binds and inactivates acrolein.

Other toxicities. Cyclophosphamide can cause SIADH with hyponatremia and, at very high doses, hemorrhagic myocarditis. Ifosfamide injures the proximal tubule, causing Fanconi syndrome (glycosuria with normal blood glucose, aminoaciduria, phosphaturia, type 2 renal tubular acidosis), and causes encephalopathy treated with methylene blue. Both suppress marrow and impair fertility. Related nitrogen mustards include melphalan (multiple myeloma), chlorambucil and bendamustine (CLL), and mechlorethamine (topical therapy for mycosis fungoides).

Match the protectant to its target: mesna (bladder, acrolein), amifostine (kidney, cisplatin), dexrazoxane (heart, anthracyclines), leucovorin (rescue from methotrexate).

Other alkylating agents

Nitrosoureas. Carmustine (BCNU) and lomustine (CCNU) are lipophilic, cross the blood-brain barrier, and treat gliomas. They cause CNS toxicity (dizziness, ataxia, seizures) and delayed myelosuppression; carmustine also causes dose-related pulmonary fibrosis that can surface years later. Streptozocin, a nitrosourea toxic to pancreatic β cells, treats islet cell tumors.

Busulfan. Used for myeloablative conditioning before hematopoietic stem cell transplant. Toxicities: profound myelosuppression, pulmonary fibrosis, Addison-like hyperpigmentation, seizures (anticonvulsant prophylaxis is given), and hepatic sinusoidal obstruction syndrome.

Procarbazine. A methylating agent for Hodgkin lymphoma (BEACOPP) and brain tumors (PCV: procarbazine, lomustine, vincristine for oligodendroglioma). It weakly inhibits MAO, so tyramine-rich foods or sympathomimetics can trigger a hypertensive crisis, and it causes a disulfiram-like reaction with alcohol; myelosuppression, sterility, and secondary leukemia also occur.

Dacarbazine and temozolomide. Both methylate guanine at O6. Dacarbazine (IV) is part of ABVD for Hodgkin lymphoma and treats melanoma. Oral temozolomide crosses the blood-brain barrier and is given with radiation for glioblastoma; tumors with a methylated, silenced MGMT promoter cannot remove the adduct and respond best. Myelosuppression, especially thrombocytopenia, is the main toxicity.

Platinum compounds

Cisplatin. Its dose-limiting toxicity is proximal tubular injury with magnesium and potassium wasting, prevented by aggressive saline (chloride) diuresis and amifostine, a thiol free-radical scavenger. It also causes irreversible high-frequency sensorineural hearing loss (obtain baseline audiometry), sensory peripheral neuropathy, and the most severe emesis among common chemotherapy drugs, prevented with a 5-HT3 antagonist, an NK1 antagonist, dexamethasone, and olanzapine. It anchors therapy for testicular (BEP), ovarian, bladder, lung, and head and neck cancers.

Carboplatin. Far less nephrotoxic, ototoxic, neurotoxic, and emetogenic; its dose-limiting toxicity is myelosuppression, especially thrombocytopenia. It is renally excreted, so the dose is calculated from GFR (Calvert formula).

Oxaliplatin. Part of FOLFOX for colorectal cancer. It causes acute cold-triggered dysesthesias of the hands, mouth, and throat within hours to days of infusion and a cumulative chronic sensory neuropathy, with minimal nephrotoxicity.

Antitumor antibiotics

Bleomycin. This glycopeptide binds iron and oxygen, generating free radicals that break DNA strands, and acts mainly in G2. Lung and skin lack bleomycin hydrolase, the inactivating enzyme, so toxicity concentrates there: dose-related pulmonary fibrosis (worse with age, renal failure, chest radiation, and high inspired oxygen), hyperpigmentation or flagellate streaks, and mucositis. Myelosuppression is minimal. It is used in BEP (testicular cancer) and ABVD (Hodgkin lymphoma).

After bleomycin, high inspired oxygen concentrations (for example during anesthesia) can precipitate lung injury; keep FiO2 as low as feasible.

Dactinomycin. Dactinomycin (actinomycin D) intercalates between G-C base pairs and blocks RNA polymerase, halting transcription. It treats Wilms tumor, Ewing sarcoma, rhabdomyosarcoma, and gestational trophoblastic neoplasia; toxicities include myelosuppression, mucositis, and radiation recall. Mitomycin cross-links DNA after reductive activation (anal cancer, intravesical bladder therapy) and can cause hemolytic uremic syndrome. Anthracyclines also intercalate but act chiefly through topoisomerase II.

Late effect: therapy-related myeloid neoplasms

Secondary MDS/AML. DNA-damaging therapy can induce myeloid neoplasms with a poor prognosis. The latency, preceding MDS phase, and cytogenetics point to the culprit class.