In recent years there have been enormous strides made toward understanding cancer. Although there has been a great deal learned about cancer, the treatments available for it have not progressed nearly as much. Attempted removal of the tumor followed by chemotherapy and radiation still prevail as the most effective treatments used. Studies on the role and effects of the p53 gene, however, provide a new avenue for possible treatment for cancer that may turn out to be more effective and have fewer side effects than current treatments. The p53 gene is a tumor suppresser gene involved in the regulation of the cell cycle, DNA repair, and programmed cell death (Schuler 2000). Since the p53 gene is involved in such a vast array of biological processes it plays an important role in the development of cancer. There is a high frequency of p53 mutations in various human cancers showing that the loss of p53 function plays a crucial part in the development of tumors (Wallace-Brodeur 1999). This paper will examine the possible roles of the p53 gene in cancer and how that information can be used for diagnosis and treatment of cancer.

The p53 gene is integral in programmed cell death or apoptosis, which is characterized by morphological changes, phosphotidylserine externalization, and internucleosomal DNA fragmentation. If the p53 gene is no longer functional and thus apoptosis does not occur, cancer cells proliferate along with their mutations. Many anticancer drugs along with treatments such as radiation try to induce apoptosis to treat cancer so it is important to examine the role of the p53 gene in apoptosis. There are basically two pathways that transduce signals to initiate apoptosis. The first pathway is a receptor-dependent or extrinsic pathway. It involves the trimerization of death factors like CD95/Fas/APO-1 or TNF receptor 1 which activate caspase 8, which in turn starts the apoptotic machinery. The second pathway is a receptor-independent or intrinsic pathway. This pathway involves the p53 gene and is thus of greater concern at the moment. The p53 gene induces the release of cytochrome C from the mitochondrial intermembrane space into the cytosol. The cytochrome c in the presence of ATP causes the oligomerization and activation of Apaf-1 and caspase 9. Apaf-1 and caspase 9 then activate caspase 3 and other effector caspases that trigger apoptosis. It is thought that p53 causes the release of cytochrome C to start this process by a pathway that involves a protein called Bax (Schuler 2000). As a result, the p53 gene may transcriptionally raise the levels of Bax, or it may cause it may cause conformational changes in the mitochondria that cause the mitochondria to target the Bax protein (Miyashita 1995). Using this information, experiments have been conducted that try to induce apoptosis in cancer cells by activation of the p53 gene. One particular study was done on the human osteosarcoma cell line Saos-2, which is p53 deficient. Introduction of the p53 gene resulted in apoptosis via an intrinsic pathway (Schuler 2000). Therefore subjecting p53 to gene therapy may be of immense important in the fight against cancer.

Another function of the p53 gene that plays a role in cancer is its effect on the function of P-glycoprotein (Pgp). Loss of p53 function increases the function of Pgp. Pgp is a membrane pump that prevents drugs from accumulating inside the cell, which keeps the drugs from functioning effectively. So it seems that the loss of p53 functions causes cells to be resistant to a variety of drugs (Chin 1992). Drugs developed to combat cancer have to take this into account so it may be important to try to develop a drug that directly inhibits Pgp as well as one that restores p53 function. Other studies have also substantiated the idea that loss of p53 function results in treatment resistance. For example, cell lines such as those in human brain cells with p53 mutations are generally more resistant to treatment than cell lines with wild type p53 (Weinstein 1997). It has also been found that p53 mutant tumors are more unstable genetically and this instability may allow the tumors to become more rapidly resistant to drug treatments (Liu 1994).

Since p53 mutations play such an important role in the development of cancer, it stands to reason that the detection of p53 mutations can be a very helpful tool in diagnosing cancer since the successful treatment of cancer is so dependent on early detection. In one study p53 mutations were found prior to clinical diagnosis of cancer in a number of patients showing its possible use as a diagnostic tool especially in individuals who are at a high risk for cancer. Some patients also have an immune response to p53 mutations so it is possible to test for the mutations by screening for anti-p53 antibodies. There is also a decrease in the number of these antibodies if treatment is successful so it can be used to measure the effectiveness of a certain treatments. Only a blood sample is required to test for p53 mutations or antibodies against them so the test is low-risk and noninvasive (Wallace-Brodeur 1999).

Having dealt with the possibilities of p53 being used a diagnostic tool, it is now important to look at what kinds of treatment involving the p53 gene may help fight cancer. Gene therapy on the p53 gene may be an important way to treat cancer because there is documented synergy between p53 gene therapy and treatments like chemotherapy (Roth 1996). This demonstrates that p53 gene therapy could prove to be a powerful force in killing cancer coupled with current treatments. One possibility for treatment involving p53 is the use of the immune system to fight cancer. Generally p53 mutations result in the production of altered proteins so the immune system could be used to target the tumor cells producing the altered proteins. This type of immunotherapy provides a nontoxic, tumor-specific treatment for cancer. Experiments done on mice have shown that dendritic cells specific for p53 mutations slowed the growth of existing tumors (Gabrilovich 1996). So if nothing else, immunotherapy may provide a way to at least slow the growth of tumors, and it may even be further developed as a cure for cancer in the future.

Studies have also found that some tumor cells lack p53. This information can be used to develop treatment that only targets tumors cells like the immunotherapy discussed above. For example, studies are now being done on the ONYX-015 adenovirus, which only replicates in cells that lack p53. Since it only replicates in those cells lacking p53, tumor cells are specifically killed by the virus while normal cells in the body are unaffected by the virus (Heise 1997).

In the midst of all the possibilities opened by the growing knowledge of the p53 gene, a couple of things must be kept in mind. The p53 gene has and is being studied extensively, but it does not function in isolation. So in order to truly understand its working, the other members involved in the p53 pathways must also be studied, and such studies are lacking. As a result, interpretations of current studies on p53 are incomplete (Wallace-Brodeur 1999). Although this may true, what we know about the p53 gene's role in cancer still provides numerous avenues upon which the pursuit for a cure for cancer can be pursued. Understanding the function of p53 could be the key to unraveling the mystery of the cure for cancer.

Works Cited

Chin, K.V., Ueda, K., Pastan, I., and M.M. Gottesman. "Modulation of activity of the promoter of the human MDR1 gene by Ras and p53." Science 255 (1992): 459- 462.

Gabrilovich, D.I., Cunningham, H.T., and D.P. Carbone. "IL-12 and mutant p53 peptide- pulsed dendritic cells for the specific immunotherapy of cancer." Journal of Immunotherapy Emphasis Tumor Immunology 19 (1996): 414-418.

Heise, C., Sampson-Johannes, A., Williams, A., McCormick, F., Von Hoff, D.D., and D.H. Kirn. "ONYX-015, an EIB gene-attenuated adenovirus, causes tumor- specific cytolysis and antitumoral efficacy that can be augmented by standard chemotherapeutic agents. Nature Medicine 3 (1997): 639-645.

Liu, T.J., Zhang, W.W., Taylor, D.L., Roth, J.A., Goepfert, H., and G.L. Clayman. "Growth suppression of human head and neck cancer cells by the introduction of a wild-type p53 gene via a recombinant adenovirus." Cancer Research 54 (1994): 3662-67.

Miyashita, T. and J.C. Reed. Cell 80 (1995): 293-299. Roth, J.A., Nguyen, D., Lawrence, D.D., Kemp, B.L., Carrasco, C.H., Ferson, D.Z., et al. "Retrovirus-mediated wild-type p53 gene transfer to tumors of patients with lung cancer." Nature Medicine 2 (1996): 985-991.

Schuler, Martin, Bossy-Wetzel, Ella, Goldenstein, Joshua, Fitzgerald, Patrick, and Douglas Green. "p53 induces apoptosis by caspase activation through mitochondrial cytochrome C release." Journal of Biological Chemistry 275 (March 2000): (10) 7337-42.

Wallace-Brodeur, R.R. and Love, S.W. "Clinical Implications of p53 mutations." Cellular and Molecular Life Sciences 54 (1999): 64-75.

Weinstein, J.N., Myers, T.G., O'Connor, P.M., Friend, S.H., Fornace, A.J., Kohn, K.W., et al. "An information intensive approach to the molecular pharmacology of cancer." Science 275 (1997): 343-349.