Pharmacology of Alkylating Agents

Alkylating agents are a class of medicines used to treat various kinds of cancer. There are many different alkylating agents – some defined as “classic”, others as “alkylating-like”, and still others as “non-classical”. Here, we review all major alkylating agent drug classes.

The history of alkylating agents finds its roots in the First World War.

In the Great War of 1914-1918, toxic gases were used as military weapons.

One of those gasses was the sulfur mustards. Exposure to this gas led to symptoms such as skin irritation, blindness and pulmonary damage. It was noted that those exposed to the gas experienced bone marrow suppression and leukopenia.

From that point, contemporary researchers believed that alkylating agents could play a role at treating neoplasms.

Toxic gases were also used in World War II.

This time, it was the less toxic nitrogen mustards. After extensive clinical trials, it was learned that nitrogen mustards, too, shrank tumors with consequent relief in symptoms. It was from here that alkylating agents were explored, developed, and what catalyzed their use as chemotherapeutic agents in modern medicine.

Even today, the alkylating drug class – in combination with other medicines – remain an important therapeutic tool in the treatment of many kinds of cancer.

Classes and Indications

There are many different alkylating agent classes.

Below, we classify the medicines into six distinct classes, though some drugs overlap between classes.

Note: though specific cancers are listed beside each drug, we have only listed their most primary uses/indications. Each anticancer drug may be used for other cancers not listed in this guide. In addition, anticancer drugs are given alongside other anticancer medicines in the treatment of these cancers.


  • Cyclophosphamide: multiple myeloma, malignant disease, ovarian cancer, lymphomas and some brain cancers
  • Melphalan: multiple myeloma, ovarian cancer
  • Chlorambucil: chronic lymphocytic leukemia (CLL), Hodgkin’s disease, lymphoma
  • Ifosfamide: testicular cancer, cervical cancer, ovarian cancer
  • Busulfan: chronic myelogenous leukemia (CML)
  • Mechlorethamine: variety of malignant diseases


  • Carmustine: brain cancers, Hodgkin’s disease
  • Lomustine: brain tumors, Hodgkin’s disease
  • Streptozotocin: pancreatic cancer


  • Dacarbazine: malignant melanoma, Hodgkin’s disease
  • Temozolomide: anaplastic astrocytoma, glioblastoma multiforme


  • Thiotepa: breast cancer, ovarian cancer, bladder cancer, lymphomas


  • Cisplatin: bladder cancer, testicular cancer, ovarian cancer, cervical cancer, breast cancer, neuroblastoma, brain tumors, non-small cell lung cancer
  • Carboplatin: ovarian cancer, cervical cancer
  • Oxaliplatin: colorectal cancer


  • Procarbazine: Hodgkin’s disease, glioblastoma multiforme

With these classes in mind, let’s take a few minutes to learn more about how alkylating agents work to exert their therapeutic effects.

Mechanism of action

As their name suggests, alkylating agents work by “alkylating” DNA.

Alkylation means that DNA is unable to replicate. It also means that DNA repair may result in DNA strands breaking apart. Alkylating agents work independently of the cell cycle, regardless of what cell cycle phase is in operation – meaning that the rate of cell death is proportionally linked to the dose administered to the patient.

Alkylating agents covalently attach an alkyl group – CnH2n+1 – to the guanine base of DNA, at the number 7 nitrogen atom of the purine ring.

Some alkylating agents act non-specifically – meaning those drugs are active under present conditions in the cell.

Some drugs must be activated.

Cyclophosphamide is one such example. It must be converted to its active metabolite, phosphoramide mustard; a metabolite only formed in cells with low levels of aldehyde dehydrogenase (ALDH). ALDH is found in high concentrations in tissues such as bone marrow, liver and intestinal epithelium – protecting these actively proliferating cells from the formation of phosphoramide mustard.

Dacarbazine is not an alkylating agent per se until it is converted, via hepatic metabolism, to diazomethane. Dacarbazine also works by methylating DNA at the O-6 and N-7 positions.

Some alkylating agents – such as busulfan – work by a dialkylating effect; reacting with two 7-N-guanine residues, which may be on the same strand or on two different strands.

Platinum-based drugs – such as cisplatin, carboplatin and oxaliplatin – are classified as “alkylating-like”. They do not add an alkyl group, but they do damage DNA in a manner similar to the effects of classical alkylating agents. They also bind to N7 of guanine.

Side effects

Side effects depend on the alkylating agent in question.

Broadly speaking though, alkylating agents are linked to:

  • Bone marrow suppression
  • Gastrointestinal effects – abdominal cramps, diarrhea, constipation etc.
  • Anemia
  • Fatigue
  • Chemotherapy-induced nausea and vomiting (CINV)
  • Infertility
  • Peripheral neuropathy – particularly platinum-based agents
  • Cognitive impairment
  • Carcinogenesis – of course, anticancer drugs damage healthy cells too

Hair loss is most associated with drugs that kill rapidly dividing cells. Examples include cyclophosphamide and ifosfamide. Hair loss is often temporary, re-growing once treatment has stopped. Regrown hair may also curl, what’s known as “chemo curl”.

More specific side effects of alkylating agents include:

  • Hemorrhagic cystitis – due to the build-up of toxic acrolein, cyclophosphamide and ifosfamide are linked to bladder bleeding. Taking mesna reduces the risk of hemorrhagic cystitis. It concentrates in the bladder and conjugates toxic acrolein, removing it from the body.
  • Cardiotoxicity – cyclophosphamide is linked to cardiotoxicity at high doses.
  • Severe vomiting – cisplatin is one of the most emetogenic chemotherapy drugs.
  • Encephalopathy – affecting up to half of patients taking ifosfamide.
  • Pulmonary fibrosis – linked to busulfan, hence the name “busulfan lung”. Busulfan is also linked to seizures. It may be taken with an antiepileptic medicine to reduce this risk.

Many alkylating agents are also associated with their own range of drug interactions. However, given the range of alkylating agents, and since they are used in combination with many other medicines, the risk-reward ratio of each drug interaction is clinically considered on a patient-by-patient, case-by-case basis.


Alkylating agents pharmacology is long and complex – involving many different classes, each of which has many different members.

Here, we’ve reviewed their history, classification, primary indications, notable side effects, and other key clinical details that students are expected to know.

For even more facts and pharmacology quiz questions on alkylating agents pharmacology, register with PharmaFactz today. Check back to our pharmacy blog soon for even more great articles on other anticancer drug classes!