Chemoprotective Agents

Chemotherapy is one of the most potent tools used to fight cancer, but the side effects from treatment can be as debilitating as the disease itself. Since cancerous cells multiply rapidly, many chemotherapy drugs target cell reproduction mechanisms, thereby harming healthy cells that also are in the process of division. Bone marrow cells, endothelial cells, and other cell types which divide rapidly can be inadvertently killed by chemotherapy treatments, leading to the common side effects like immunosuppression and nausea. Chemoprotective agents are chemicals administered concurrently with chemotherapies in order to selectively protect healthy cells from the toxic chemotherapy drugs. Since multiple chemotherapy drugs are often given simultaneously in a combination chemotherapy regimen, several chemoprotective agents may be administered at once as well.

Chemoprotective drugs are usually administered with a specific type of chemotherapy drug.  For example, Mesna, which is used with oxazaphosphorines Mesna (2-mercaptoethane sodium sulfonate) binds to the toxic metabolites of this class of chemotherapy drugs, helping to prevent bladder inflammation and other urogenital problems.   Mesna is relatively inactive in the body while it travels through the bloodstream.  The kidney extracts it from the blood (it is the kidney’s job to remove foreign substances from the bloodstream) and it is there that the Mesna is activated.  Some chemotherapy drugs damage the kidney or bladder after the kidney extracts them or their metabolites (breakdown products of the drugs).  Mesna binds to the metabolites and makes them less toxic to the body’s organs.  Mesna is also given to some cancer patients who are having surgery, to reduce complications.

Dexrazoxane is particularly well-suited to keeping anthracycline antibiotics from damaging cardiac tissue. Anthracyclines can disrupt certain receptors in heart tissue, promote free radical formation, and cause accumulations of cytotoxic metabolites, which is why these drugs are not used to treat normal infections, despite being antibiotics. The exact mechanism by which dexrazoxane prevents anthracycline-related damage is unknown, but it may be due to its ability to sequester iron atoms via chelation.

More recently developed chemoprotective drugs, such as Amifostine, are designed to protect multiple organ systems from a broader spectrum of chemotherapies. Amifostine prevents DNA-binding drugs such as cyclophosphamide, as well as drugs like cisplatin, which contain platinum, from binding to cells. Amifostine actually makes use of extracellular conditions, such as alkaline phosphatase activity, higher pH, and better vascular delivery of the drug to healthy tissue, in order to protect healthy tissue, while not extending this same type of defense to cancer cells. Amifostine is actually not an active drug on its own, and instead is converted into an active metabolite inside cells. The metabolite is formed more often in healthy cells, where it sequesters chemotherapy drugs, possibly by binding platinum present in some of these agents.

Another chemoprotective drug used to reduce the side effects of cisplatin is N-Acetylcysteine. Researchers have shown N-acetylcysteine given up to two hours after administration of cisplatin prevents programmed cell death and reversed cytotoxic damage to tumor cell lines. N-Acetylcysteine seems to prevent cisplatin binding cellular and mitochondrial receptors which normally begin the process of apoptosis. Since this drug does not cross the blood-brain barrier, it is thought that it could be used in patients with brain cancer to protect many organs from damage without reducing the tumor-killing properties of the cisplatin.

Chemoprotective agents are still a new field in both clinical practice and scientific theory, and research will likely yield agents with greater selectivity for healthy tissue, as well as the ability to protect a larger number of tissue types. Nanoparticle delivery of chemotherapy drugs may also assist in minimizing the side effects.