What Are Alkylating Agents? Definitions, Types & Common Examples
Any highly reactive drug that binds to certain chemical groups (amino, phosphate, sulfhydryl, and hydroxyl groups) commonly found in nucleic acids, as well as other macromolecules, causes changes in the RNA and DNA of cells is known as an alkylating agent. Alkylating agents were the first anticancer medications to be used, and despite their risks, they remain the cornerstone of anticancer therapy.
Examples of Alkylating Agents
A few examples of alkylating agents can be given as:
cisplatin, nitrogen mustards (cyclophosphamide and chlorambucil),
alkyl sulfonates (busulfan),
nitrosoureas (lomustine, semustine, and carmustine),
triazines (dacarbazine), and
ethyleneimines (thiotepa).
Types of Molecular Changes
The types of molecular changes that are induced by the alkylating agents can be given as cross-linking between the DNA strands and the loss of a basic component (which is purine) from or the nucleic acid breaking. The result is, nucleic acid will not be replicated.
Either the altered DNA will be not able to carry out the cell functions, resulting in cell death (which is called cytotoxicity), or the altered DNA will change the characteristics of the cell, resulting in an altered cell (which is called mutagenic change). This change can result either in the ability or tendency to produce cancerous cells (which is called carcinogenicity). Normal cells can also be affected and become cancer cells.
Alkylating Agents Drugs
Alkylating agents were one first class of drugs to be used against cancer. There exist five traditional categories of alkylating agents, which are given as follows:
Nitrogen mustards (for example, chlorambucil, bendamustine, ifosfamide, cyclophosphamide, melphalan, and mechlorethamine)
Alkyl sulfonates (for example, busulfan)
Nitrosoureas (for example, lomustine, carmustine, and streptozocin)
Ethylenimines (for example, thiotepa and altretamine), and
Triazines (for example, temozolomide and dacarbazine).
Cause of Alkylating Agents
Alkylating agents may cause critical vomiting and nausea and decreases the number of white blood cells and red blood cells as well. The decrease in the white blood cell count results in susceptibility to the infection. Alkylating agents have been found to be used in the treatment of leukaemia, lymphoma, melanoma, testicular cancer, breast cancer, and brain cancer. Often, they are the most used ones in combination with other anticancer drugs.
Some types of Alkylating Agents
Nonspecifically Acting Agents
A few of the alkylating agents are active under the conditions present in cells, and the similar mechanism that makes them toxic allows them to be used as anti-cancer drugs. They stop the tumour growth by cross-linking guanine nucleobases in the double-helix strands of DNA, directly attacking DNA. This process makes the strands unable to separate and uncoil. As this is quite necessary for DNA replication, the cells may no longer divide. These particular drugs act nonspecifically.
Agents Requiring Activation
A few of the substances that require conversion into the active substances in vivo (for example, cyclophosphamide).
Cyclophosphamide is the most potent immunosuppressive substance. In small doses, it is much efficient in the therapy of autoimmune hemolytic anaemia, systemic lupus erythematosus, granulomatosis with polyangiitis, including the other autoimmune diseases. High dosages will cause pancytopenia and hemorrhagic cystitis.
Dialkylating Agents
Dialkylating agents may react with two various 7-N-guanine residues, and if these are in varied DNA strands, the result can be cross-linkage of the DNA strands that prevents the DNA double helix from uncoiling. The effect is limpet binding of the drug molecule to the DNA if the two guanine residues are in the same chain. Busulfan is one of the examples of a di-alkylating agent: it is also the methanesulfonate diester of 1,4-butanediol. Methanesulfonate may be eliminated as a leaving group. Both the ends of the molecule may be attacked by the DNA bases by producing a butylene cross-link between the two different bases.
Monoalkylating Agents
Monoalkylating agents can only react with one 7-N of guanine.
Limpet Attachment
Monoalkylation and limpet attachment do not prevent the two DNA strands’ separation of the double helix but do prevent the vital DNA-processing enzymes from DNA accessing. The final result is given as the inhibition of cell growth or stimulation cell suicide, apoptosis.
Nitrogen Mustard
Nitrogen mustards are the cytotoxic organic compounds having the functional group - chloroethylamine (Cl(CH2)2NR2). Although originally it is produced as chemical warfare agents, they were the first chemotherapeutic agents for cancer treatment. Nitrogen mustards are said to be the nonspecific DNA alkylating agents.
Limitations
Alkylating antineoplastic agents have some limitations. Alkylating antineoplastic agent’s functionality has been found to be limited in the presence of the DNA-repair enzyme, which is O-6-methylguanine-DNA methyltransferase (MGMT). The cross-linking of double-stranded DNA by the alkylating agents can be inhibited by a mechanism of cellular DNA repair, MGMT.
If the MGMT promoter region gets methylated, the cells will no longer produce the MGMT, and they are thus more responsive to the alkylating agents. In gliomas, methylation of the MGMT promoter is a valuable indicator of tumour responsiveness to alkylating agents.
FAQs on Alkylating Agent: Mechanism, Types & Uses
1. What is an alkylating agent in the context of chemistry and medicine?
An alkylating agent is a chemical compound that donates an alkyl group (a set of carbon and hydrogen atoms) to another molecule. In medicine, particularly in chemotherapy, these agents work by attaching an alkyl group to the guanine base of a DNA molecule. This action prevents the DNA strands from unzipping for replication or transcription, thereby disrupting the cell's life cycle and ultimately leading to cell death (apoptosis).
2. How does the mechanism of an alkylating agent lead to the destruction of a cell?
The primary mechanism of an alkylating agent involves a process called alkylation. The agent transfers an alkyl group to electron-rich sites on the DNA molecule, most commonly the N7 position of the guanine base. This chemical alteration leads to several destructive outcomes:
- DNA Damage: It can cause mispairing of DNA bases (e.g., guanine pairs with thymine instead of cytosine).
- Cross-linking: Bifunctional alkylating agents can form links within a single DNA strand (intra-strand) or between two different strands (inter-strand).
- Replication Inhibition: The damaged or cross-linked DNA cannot be separated properly, which halts the process of DNA replication and cell division.
3. What are the main types or classes of alkylating agents?
Alkylating agents are broadly classified based on their chemical structure. The main types include:
- Nitrogen Mustards: Examples include Cyclophosphamide, Melphalan, and Chlorambucil.
- Nitrosoureas: Such as Carmustine (BCNU) and Lomustine (CCNU), which are notable for their ability to cross the blood-brain barrier.
- Alkyl Sulfonates: Busulfan is a primary example in this class.
- Triazenes: Includes drugs like Dacarbazine and Temozolomide.
- Platinum-based Drugs: Though they don't transfer an alkyl group, drugs like Cisplatin and Carboplatin function similarly by binding to DNA and are often classified with alkylating agents.
4. Why are alkylating agents generally more effective against cancer cells than normal, healthy cells?
Alkylating agents are most effective against cells that are actively and rapidly dividing. Cancer cells are characterized by their uncontrolled and rapid proliferation. During cell division (mitosis), the cell's DNA is unwound and exposed, making it much more vulnerable to alkylation. While these agents do affect healthy dividing cells (like those in bone marrow or hair follicles), they have a disproportionately larger impact on cancer cells, which are almost constantly in a state of replication. Normal cells divide less frequently and have more time to repair DNA damage between divisions.
5. What is the key difference between a monofunctional and a bifunctional alkylating agent?
The key difference lies in the number of reactive groups they have and how they damage DNA. A monofunctional agent has one reactive group and can attach an alkyl group to a single point on a DNA strand. This causes damage but can often be repaired by the cell. In contrast, a bifunctional agent has two reactive groups, allowing it to bind to two different sites. This enables it to form a cross-link, either between two bases on the same DNA strand or, more lethally, between the two separate strands of the DNA double helix. This inter-strand cross-linking is very difficult for the cell to repair and is a major cause of cell death.
6. What are Nitrosoureas, and what makes them a unique type of alkylating agent?
Nitrosoureas are a class of alkylating agents known for their high lipophilicity (ability to dissolve in fats or lipids). This chemical property is significant because it allows them to cross the blood-brain barrier, a protective membrane that prevents most substances from entering the brain. This unique ability makes nitrosoureas, such as Lomustine and Carmustine, particularly useful in the treatment of brain tumours, where other chemotherapeutic agents cannot reach.
7. How can a cancer cell develop resistance to an alkylating agent?
Cancer cells can develop resistance to alkylating agents through several mechanisms. One of the most important is an increase in the cell's ability to repair DNA damage. Cells can produce higher levels of enzymes, like O6-methylguanine-DNA methyltransferase (MGMT), which can remove the alkyl groups from DNA before they cause permanent harm. Other resistance mechanisms include decreasing the drug's uptake into the cell or increasing its detoxification and removal from the cell before it can reach the DNA.
8. What are the common uses of alkylating agents?
The primary use of alkylating agents is in cancer chemotherapy to treat a wide variety of cancers, including lymphomas, leukaemias, sarcomas, and carcinomas. However, their use is not limited to oncology. At lower doses, some alkylating agents like cyclophosphamide are used as immunosuppressants to treat autoimmune diseases, such as lupus or rheumatoid arthritis, by dampening the overactive immune response. They are also used to prepare patients for bone marrow transplants.
9. Why do treatments with alkylating agents often cause side effects like hair loss and nausea?
The side effects of alkylating agents stem from their mechanism of action. Because they target all rapidly dividing cells, not just cancerous ones, they also damage healthy tissues that have a high rate of cell turnover. This includes:
- Hair follicles: leading to hair loss (alopecia).
- Lining of the digestive tract: causing nausea, vomiting, and diarrhoea.
- Bone marrow: suppressing the production of new blood cells, which can lead to anaemia, increased risk of infection, and easy bruising.
