Alkylating agents
Reactive drugs that bolt alkyl groups onto DNA, cross-linking its strands so a dividing cell can no longer copy or read its genes.
What they are
The oldest family of cancer drugs: nitrogen mustards (cyclophosphamide, ifosfamide, melphalan, chlorambucil, bendamustine), an alkyl sulfonate (busulfan), nitrosoureas (carmustine, lomustine) and methylating drugs (temozolomide, dacarbazine, procarbazine). They treat leukaemias, lymphomas, myeloma, brain tumours and many solid cancers, and some are used to prepare patients for stem cell transplants.
Mechanism of action
Each drug, directly or after activation, forms a highly reactive electrophile that bonds covalently to electron-rich sites on DNA, above all the N7 of guanine. Bifunctional drugs (mustards, nitrosoureas, busulfan) bond twice and cross-link the two strands; methylating drugs add a single methyl group, often at the O6 of guanine. The damaged DNA cannot be copied or transcribed, and the cell dies by apoptosis. They act in every phase of the cell cycle, but dividing cells are hit hardest, so the bone marrow, gut lining, hair follicles and gonads suffer.
Target: DNA (guanine N7 and O6)
Drugs in this class
- CyclophosphamideA nitrogen mustard prodrug activated in the liver. It cross-links DNA in lymphomas, leukaemias and breast cancer, and…DNA (guanine N7), cross-linked by phosphoramide mustard
- IfosfamideA cyclophosphamide relative that is always given with mesna. Its metabolites can cause bladder bleeding, kidney damage…DNA (guanine N7), cross-linked by ifosfamide mustard
- BusulfanAn alkyl sulfonate that wipes out the bone marrow before a stem cell transplant. It can cause seizures, liver…DNA (guanine N7), cross-linked by the alkyl sulfonate
- CarmustineA nitrosourea that crosses into the brain. Its myelosuppression is delayed and cumulative, and it can scar the lungs…DNA (guanine), alkylated and cross-linked; proteins carbamoylated
- TemozolomideAn oral methylating drug that turns into MTIC by itself and reaches the brain. With radiotherapy it is the standard…DNA (guanine O6 and N7), methylated by MTIC
- BendamustineA nitrogen mustard with a purine-like ring, given intravenously for chronic lymphocytic leukaemia and indolent B-cell…DNA, cross-linked between strands
- ChlorambucilA slow-acting oral nitrogen mustard, historically the classic drug for chronic lymphocytic leukaemia; still used when…DNA (guanine N7), cross-linked by the mustard
- DacarbazineAn intravenous triazene that the liver turns into the methylating agent MTIC. Used for metastatic melanoma and in…DNA (guanine), methylated by MTIC
- MelphalanPhenylalanine mustard for multiple myeloma, oral or intravenous (high doses before an autologous transplant)…DNA (guanine N7), cross-linked by the mustard
- ProcarbazineOral methylating drug for Hodgkin lymphoma and brain tumours. A weak MAO inhibitor with a disulfiram-like alcohol…DNA (methylated by activated procarbazine metabolites)
- LomustineAn oral nitrosourea for brain tumours. One dose covers a long cycle: dispensing errors have caused fatal overdoses…DNA and RNA, alkylated; proteins carbamoylated
- ChlormethineThe first nitrogen mustard. Today mainly a skin gel for early mycosis fungoides; the old IV form was a strong vesicant.DNA (guanine N7), cross-linked by the mustard
- ThiotepaAn old ethylenimine alkylating drug: used in stem cell transplant conditioning, in some solid tumours and instilled…DNA (guanine N7), cross-linked by thiotepa and its active metabolite TEPA
- StreptozocinA glucose-linked nitrosourea that is taken up by insulin-making cells; used for pancreatic islet cell cancer. Watch…DNA (guanine), methylated by the nitrosourea
- LurbinectedinAn IV drug that binds the DNA minor groove and stops cancer cells dividing; used in small cell lung cancer. Watch…DNA minor groove (guanines)
Others in the class
- mechlorethamine (chlormethine)
- thiotepa
- treosulfan
- trabectedin
Test yourself
Think of the answer, then tap the question to see it.
Which DNA base and atom do most alkylating agents attack?
Guanine, mainly at its N7 position (methylating drugs also at O6).
Why do bifunctional alkylators kill cells more effectively than single-arm ones?
They bond twice and cross-link the two DNA strands, which blocks strand separation for copying and transcription.
Which alkylating agents are chosen for brain tumours, and why?
The nitrosoureas (carmustine, lomustine) and temozolomide: they are lipid-soluble and cross the blood–brain barrier.
What long-term risk do all alkylating agents share?
Second cancers, especially myelodysplasia and acute myeloid leukaemia, plus infertility.
Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.
Sources: DailyMed - CYCLOPHOSPHAMIDE injection, powder, for solution (DailyMed (U.S. National Library of Medicine), 2026); DailyMed - TEMOZOLOMIDE capsule (DailyMed (U.S. National Library of Medicine), 2026); ATCDDD - ATC/DDD Index (WHO Collaborating Centre for Drug Statistics Methodology, 2026).
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Representative model, for educational purposes only.