Prodrugs in chemotherapy

Researchers and medical professionals have made great strides in the fight to cure and prevent cancer. For a significant amount of time, chemotherapy served as the best and most effective method to treat cancer. However, chemotherapy has proven rather ineffective especially when dealing with patients diagnosed with solid cancers especially after they metastasize. This has pushed researchers and clinicians to the discovery that intensifying the amount of dosage makes a significant number of anticancer agents curative. The effectiveness however hinges on the ability to administer higher doses than those administered in normal clinical settings. When treating cancers, the initial chemical used with pharmacodynamics properties is known as the lead chemical. Once administered, the treatment moves to the next stage where the lead chemical goes through derivatization as a way to enhance its properties. If successful, the derivatization helps to reduce any side effects associated with the treatment method and further improves its selectivity of action. Also, the derivative may fail to have any intrinsic activity and gets converted into an active drug in vivo at the required time or place and such analogs are referred to as prodrugs.

           Prodrugs refer to therapies that are designed to stay inactive after being administered and only react once they reach the intended target. Since their inception in the field of medicine, antibody-drug conjugates have proven to be the most promising when used in anticancer therapy with some even getting approved by the FDA (Kratz et al, 2012). Prodrugs have been considered as an ideal method of fighting cancer especially because they increase the normal dose needed to cure tumors resistant to chemotherapy by 50 fold. However, their application has proven challenging because human tumors rarely express a high level of an acting enzyme. Research is however underway to come up with new therapies to help overcome the limitations curtailing the effectiveness of prodrug therapy (Kratz et al, 2012). A good example is the use of enzymes that activate prodrugs being directed to the patient’s tumor xenografts by combining them with tumor-associated antibodies. Once the combining process is complete and has cleared from the blood, a prodrug is administered in inert form and only gets activated once the enzyme has made its way to the tumor.

           Antibody-directed enzyme prodrug therapy allows for different combinations of enzymes, antibodies, prodrugs, and other human tumor xenografts that are sensitive and resistant to conventional methods of chemotherapy. The success of early trials indicates that Antibody directed enzyme prodrug therapy may prove to be an ideal treatment for solid cancers, especially when dealing with known tumor-specific or tumor-associated cancers (Avendano & Menendez, 2008). The prodrugs are designed in such a way that they can modify a drug’s chemical and physical characteristics to make them more effective. A prodrug strategy is however important as it regulates the time or conditions under which the drug will become active and thus reduce the off-target toxicity of the drug while still increase its ability to kill the cancer cells. The strategy helps to improve the bio viability of the drugs, solubility in water, rate of absorption, administration route, and its ability to overcome any barriers that may affect its effectiveness.

           Prodrug strategies can be divided into two categories depending on how they are converted to make them active. Passively activated prodrugs target the differences that exist between normal and cancerous cells. A good example is the specific surface receptors present in cancer cells but absent in normal cells or low oxygen levels or the lower pH of the microenvironment around tumors (Karaman, 2014). Prodrugs can also be activated by administering secondary activating substances or drugs to the patient thus making them the most promising approach to prodrug therapy today.

           The effectiveness of prodrugs depends on the monoclonal antibody’s ability to target tumor-associated antigens that are further tied to the chemotherapeutic agent in a process that allows medical professionals to target and deliver the cytotoxic in high dosage than usual thus increasing their effectiveness (Rangel, 2013). It is therefore important to ensure that the link between the drug and the antibody is properly linked. For it to be effective, the prodrugs must be broken at a specific time to increase their efficiency and also reduce the likelihood and amount of cytotoxic drugs introduced into the system.

           The success of prodrugs in chemotherapy amongst cancer patients has prompted the FDA to approve a variety of Antibody directed enzyme prodrugs. They include ado-trastuzumab emtansine; brentuximab vedotin (Adcetris); inotuzumab ozogamicin (Besponsa); and gemtuzumab ozogamicin (Mylotarg) for HER2 in metastatic breast cancer; Hodgkin and anaplastic large cell lymphoma; acute lymphoblastic leukemia; and acute myeloid leukemia (AML) respectively (Rangel, 2013). Researchers are still trying to find more effective treatments and this is likely to increase the number of drugs approved by the FDA and also ensure that those already being tested move on to the next phase. ADCs have proven useful especially because of the carrier-linked prodrugs where the parent drug is linked to a secondary molecule that determines how the drug will react instead of modifying the parent drug itself. Further research seeks to only introduce specific alterations to the parent drug and this could help remove elements that bring about side effects or reduce the effectiveness of the drug.

           A good example of these prodrugs is Cyclophosphamide, a prodrug of phosphoramide mustard which is a DNA cross-linking agent which only becomes activated by cells with low levels of aldehyde dehydrogenase. Another example is Capecitabine which has proven effective in treating colorectal and breast cancers. The prodrug has low cytotoxic activity when used on its own but more effective once it becomes enzymatically metabolized to become an active drug (5-fluorouracil) which impedes DNA synthesis.

           Another approach involves the use of nanoparticle technology to enhance the effectiveness of prodrugs. The chemotherapy drugs are put inside nanoparticles which are designed to enhance their bio viability and solubility which ensures that the majority of the drug reaches the tumor rather than being broken down before accomplishing its intended purpose (Karaman, 2014). Since the drug is released after the cancer cells take the nanoparticle, it is more effective as the prodrug starts acting on the cancer cells at a higher dose. The use of proteins like albumin to coat the nanoparticles further intensifies the specificity of the prodrug delivery to the tumor and this makes it more effective.

           The difficulty in treating cancer has prompted different research to try and find treatment methods as well as preventive measures. Prodrugs are proving effective in the fight against cancer especially due to their ability to enhance the effectiveness of the treatment methods being used. While there is still a need for more research on how to enhance the effectiveness of chemotherapy, there is still a need for more research to ensure that the treatment methods used are effective and cause the least side effects to the patient.

 

References

Avendaño, C., & Menéndez, J. C. (2008). Medicinal chemistry of anticancer drugs. Amsterdam; Boston: Elsevier

Karaman, R. (2014). Prodrugs design: A new era. New York: Nova Biomedical

Kratz, F., Kratz, F., Senter, P., Steinhagen, H., & Wiley InterScience (Online service).      (2012). Drug delivery in oncology: From basic research to cancer therapy. Weinheim:   Wiley-VCH.

Rangel L, (2014) “Cancer Treatment - Conventional and Innovative Approaches”.  InTech.