Alkylating agents

Question 1

Cyclophosphamide, ifosfamide

Answer 1

Mechanism: Covalently X-link (interstrand) DNA at guanine N-7. Require bioactivation by liver.

Clinical use: Solid tumors, leukemia, lymphomas, and some brain cancers.

Toxicity: Myelosuppression; hemorrhagic cystitis, partially prevented with mesna (thiol group of mesna binds toxic metabolite).

Question 2

Nitrosoureas (carmustine, lomustine, semustine, strptozocin)

Answer 2

Mechanism: Require bioactivation. Cross blood-brain barrier -> CNS.

Clinical use: Brain tumors (including glioblastoma multiforme).

Toxicity: CNS toxicity (dizziness, ataxia).

Question 3

Busulfan

Answer 3

Mechanism: Alkylates DNA.

Clinical use: CML. Also used to ablate patient’s bone marrow before bone marrow transplantation.

Toxicity: Pulmonary fibrosis, hyperpigmentation.