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Pharmacogenetics and Cancer Therapy - Page 2

© David Olle

Genes code for the synthesis of proteins. The most important proteins in terms of interaction with drugs are those that are involved with receptors, transporters, and cell-signaling pathways. A transporter is necessary to bring a drug to the cell surface. An active receptor on the cell surface then binds to the drug to activate a cell-signaling pathway that result in a command to the cell to act in a certain way. In terms of cancer, the most important signaling pathways are those that activate the cell cycle, leading to cell division. Many of these pathways involve a series of enzymes, where each enzyme in turn activates the next enzyme in the pathway.

Currently, a large amount of research effort in the area of polymorphism is focused on the functioning of enzymes that affect the activation or disactivation of drugs. Also important is the presence of active receptors on the cancer cell. 1Cancer is often caused by the over functioning of these receptors. In these cases, the role of drugs is to bind to these receptors in order to disactivate them.

Examples of the effect of polymorphism on cancer chemotherapy

I will now provide a few examples of how the knowledge of polymorphism is finding a place in current clinical practice.

Thiopurines, such as mercaptopurine and azathiopurine, are commonly used for the treatment of leukemias. These prodrugs must be converted into thioguanine nucleotides (TGNs) by the enzyme HPRT. (I am using acronyms for some enzymes). The enzyme TMPT modifies thiopurines so that TGNs are not formed. Various polymorphisms result in a loss of activity of TMPT, so that TGNs accumulate to toxic levels.

A pharmacogenomic test, developed by St. Jude Children's Hospital, allows physicians to predetermine patients' TMPT activity levels that could be assocoiated with TMPT deficiency. (4) Adjusting the dose of TMPT deficient patients makes thiopurines as tolerable and effective as in patients with normal activity levels. This diagnostic test is now being used extensively.

5-fluorouracil is widely prescribed for breast and colorectal cancer. This drug acts by inhibiting an enzyme essential for cancer cell replication. The enzyme DPD inactivates 5-fluorouracil. A common polymorphism reduces DPD function, resulting in the accumulation of toxic levels of 5-fluorouracil.

Herceptin is often considered for the treatment of metastic breast cancer, particularly for patients that have developed resistance to tamoxifen. Herceptin acts specifically by blocking the HER2 receptor on the cancer cell. HER2 is known as a proto-oncogene, in that it codes for a receptor that has the normal function of binding to estrogen hormone. However, a mutation results in the overactivation of this receptor. The cell is then over stimulated by estrogen, leading to cancer. Before Herceptin can be used for treatment, testing must be done to determine if the patient is overexpressing the HER2 gene.

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