Alkylating Agents

From Chempedia

Chemotherapeutic Mechanism of Alkylating Agents

There are approximately 50 chemotherapeutic drugs in use; each drug can be categorized based on its mechanism of action. Alkylating agents are one class of chemotherapeutic drugs used to treat cancer, a disease characterized by uncontrolled cell division and tumor development due to damaged DNA (deoxyribonucleic acid).^[1] In general, chemotherapy drugs interfere with cell division or reproduction in order to cure cancer, decrease risk of cancer reoccurrence, or prolong a cancer patient\’s life. Alkylating agents interrupt DNA replication. In cell nuclei, two strands of DNA are held together in a double helix structure by hydrogen bonding interactions. In order to copy the genetic code before cell division, normal double-stranded DNA separates into individual strands, and enzymatic molecules help create a complimentary strand for each of the original DNA strands. With two copies of the necessary genetic information, one cell can divide into two autonomous cells.^[2] Alkylating agents counteract cancerous cell division by cross-linking the two DNA strands in the double helix so that they cannot separate. This action counteracts cancer\’s uncontrolled cell division that causes tumors.

The molecular structure of carmustine, an alkylating agent commonly used as a chemotherapy drug.

The Alkylating Agent Carmustine

The drug carmustine is one example of a chemotherapeutic alkylating agent that is commonly used to treat Hodgkin\’s disease, meningeal leukemia, and brain tumors.^[3] Carmustine belongs to the nitrosourea family of molecules; nitroso indicates the presence of an N=O group and urea indicates the presence of an NCON group in the molecular structure (Figure 1). The overall molecular formula for carmustine is C₅H₉Cl₂N₃O₂ and the molecular mass is 214.05 grams/mole. The drug is usually administered to cancer patients via an intravenous drip. Carmustine is a highly lipophilic molecule, meaning that it can efficiently enter the lipid membranes of cells. This solubility can be accounted for by considering the interaction between the highly polar carmustine molecule and the polar headgroup of the molecules that make up the cell membrane.^[4] Once inside the cell, carmustine is converted into a carbocation and an isothiocyanate compound. A carbocation is a positively charged carbon ion; the carbon has only six valence electrons instead of the preferred filled valence shell of eight electrons. The carbocation is highly unstable and reactive.^[5] It is this highly reactive carbocation that covalently bonds to guanine bases in both strands of the DNA double helix (Figure 2).^[6] These covalent bonds are much stronger than the intermolecular hydrogen bonding interactions that usually hold two single strands of DNA together. Accordingly, the enzymes that are usually able to separate the DNA double helix are unable to perform their function and replication does not occur. The isothiocyanate compound (S=C=N^-) that is produced as a byproduct when carmustine is converted into the carbocation is toxic when it interacts with proteins, and thus, is a likely source of negative chemotherapy side effects. The effects of carmustine on DNA replication are not specific to cancerous cells; however, healthy cells are usually able to repair the damage done by chemotherapeutic drugs.

A schematic showing the covalent binding of a carbocation (pink diamond) between two guanine residues in double-stranded DNA, blocking replication^[6]

Cognitive Side Effects of Carmustine

A major controversy in the field of chemotherapy treatment is whether or not drugs like carmustine are able to cross the blood-brain barrier. The blood-brain barrier is made up of tightly packed endothelial cells that protect the brain by blocking passage of most molecules from the blood into the brain. Only non-polar molecules like O₂ or CO₂, molecules with specific transport systems like sugars, and highly lipophilic molecules can cross the blood-brain barrier.^[7] Because carmustine is a lipophilic molecule, it may be able to cross the blood-brain barrier and contribute to cognitive impairment. Oncologists and cancer patients refer to this cognitive impairment as chemobrain. Chemobrain is a less observable side effect of cancer or cancer treatment than hair loss or nausea. Cancer patients with chemobrain often experience short term memory loss and decreased processing speed.^[8] If these drug molecules enter the brain, they may directly or indirectly cause atrophy of gray matter or disrupt neurotransmission. Both of these actions would have significant health effects on the cancer patients. Further research is needed to study the interaction between different chemotherapy drugs and the blood-brain barrier as well as to develop alkylating agents whose side products (currently isothiocyanate from carmustine) are not toxic.

Footnotes

1. ^ Ruddon, Raymond W., Cancer Biology, 3rd Edition, Oxford University Press: Oxford, 1995; pp. 520.
2. ^ Campbell, N. A. and Reece, Jane B., Biology, 7th Edition, Benjamin Cummings: Boston, 2005; pp. 1312.
3. ^ Alkylating Agents, http://artemis.unmc.edu/cancer/alkylate.htm (accessed 09/18/2005).
4. ^ Lipid Bilayer, http://en.wikipedia.org/wiki/Lipid_bilayer (accessed 09/18/2005).
5. ^ Wade, Leroy G., Organic Chemistry, 6th Edition, Prentice Hall: New York, 2005; pp. 1328.
6. ^ ^a Mechanisms of Alkylating Agents, http://www.cancerquest.org/index.cfm?page=486 (accessed 09/18/2005).
7. ^ Cooper, Jack R., Bloom, Floyd, E., and Roth, Robert H., The Biochemical Basis of Neuropharmacology, 8th Edition, Oxford University Press: Oxford, 2002; pp. 400.
8. ^ Rovner, Sophie L., Cancer’s Toll on the Brain, Chemical and Engineering News, 2005, 83 (37), 33-35.