Alkylating agents and DNA cross-linking
Alkylating agents are anticancer drugs that attach alkyl groups (small carbon-based chemical groups) to DNA, and many can form cross-links (chemical bridges across the DNA) that block replication.
Remember
Alkylating agents attach alkyl groups to DNA, mainly at N7, a nitrogen atom on guanine (one of the four DNA bases), and many can form cross-links that block replication and, if repair fails, lead to apoptosis.
Memory aid
a staple clipped across the DNA ladder
Picture the drug as a staple across the ladder of DNA, so the ladder cannot be opened and copied.
An alkylating agent is a drug that attaches an alkyl group (a small carbon-based chemical group) to DNA. It does so mainly at N7, a nitrogen atom on guanine, one of the four DNA bases. The attached group is called an adduct, an unwanted chemical extra stuck on the DNA.
Many of these drugs are bifunctional, which means they have two reactive arms. They can bind two bases at once and so form cross-links, which are chemical bridges that tie the DNA together.
A cell cannot copy DNA past a cross-link, so replication (copying the DNA before division) stalls, and transcription (reading a gene to make RNA) is blocked too. The cell detects the damage, and its DNA damage responses, its repair and alarm pathways, switch on. If repair fails, the cell undergoes apoptosis, which is programmed cell death.
These drugs act in any phase of the cell cycle (the series of stages a cell passes through to divide), so they are called cell-cycle-non-specific. Rapidly dividing cells still suffer most, and the bone marrow is damaged at high doses.
Examples are cyclophosphamide, ifosfamide, chlorambucil and busulfan. Cyclophosphamide is a prodrug, an inactive drug that the body has to convert into its active form. Liver enzymes turn it into phosphoramide mustard, the form that alkylates DNA, and into acrolein, a toxic by-product that passes into the urine and can cause haemorrhagic cystitis (bleeding inflammation of the bladder). Mesna, a protective drug, prevents or treats that cystitis.
Key facts
- Main target
- alkyl groups are added to the bases of DNA, mainly at N7 of guanine, forming adducts, and many of these drugs can also form cross-links.
- Consequence
- the cell cannot replicate or transcribe its DNA past a cross-link, DNA damage responses are triggered and, if repair fails, the cell undergoes apoptosis.
- Cell cycle
- they work in any phase, so they are cell-cycle-non-specific, although rapidly dividing cells are hit hardest.
- Cyclophosphamide toxicity
- acrolein can cause haemorrhagic cystitis, which mesna prevents or treats.
- Resistance
- tumour cells can resist these drugs by repairing DNA more efficiently, pumping the drug out, or attaching it to glutathione, a small protective molecule that neutralises reactive chemicals.
- Late risk
- secondary leukaemia, a second cancer of the blood, can follow treatment with alkylating agents.
Exam traps
- Antimetabolites such as methotrexate interfere with the building blocks of DNA by inhibiting enzymes; they do not chemically modify the DNA itself, which is what alkylating agents do.
- Anthracyclines, a class of anticancer drugs that includes doxorubicin, slide between the base pairs of DNA, which is a genuine but different way of damaging it. Alkylating agents do not wedge in between the bases; they bond to them covalently (with strong, shared-electron chemical bonds).
- Mitotic inhibitors such as vincristine act on microtubules, protein tubes that build the spindle which pulls the chromosomes apart in mitosis. They stop cell division without chemically bonding to DNA, unlike alkylating agents.
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