Cisplatin 17. Drug Resistance
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Even though cisplatin has proven to be a highly effective chemotherapeutic agent for treating various types of cancers, it has encountered the same fate as many other drugs used in cancer chemotherapy—namely, drug resistance. Resistance occurs when cells once destroyed by a particular drug no longer respond to treatment with that drug. Drug resistance is a major complication in cancer chemotherapy and accounts for the failure of chemotherapy to cure the majority of cancer patients.1 Drug resistance has been described as "the single most common reason for discontinuation of a drug."2
Indeed, drug resistance has significant clinical implications. When cells become resistant to cisplatin, the doses must be increased; a large dose escalation can lead to severe multiorgan toxicities (such as failures of the kidneys and bone marrow), intractable vomiting, and deafness.3 (See module on toxic side effects.) Drug resistance exists in two forms: acquired resistance, in which a drug is initially beneficial but becomes ineffective over time and intrinsic resistance, in which the drug is ineffective from the outset. Drug resistance can operate by a number of mechanisms, none of which is fully understood. Postulated mechanisms of cisplatin drug resistance include decreased intracellular accumulation of cisplatin, increased intracellular levels of certain sulfur-containing macromolecules, and increased DNA repair.1,3
- Decreased Intracellular Accumulation If cisplatin cannot accumulate in the cell, it cannot reach the DNA found inside the cell, bind the DNA, and cause cell death. Therefore, it is beneficial for the cancer cell to develop mechanisms either to keep cisplatin out of the cell or to remove cisplatin from the cell; indeed, reducing cisplatin accumulation by cancer cells seems to be a major form of acquired resistance. The mechanism of decreased intracellular accumulation of cisplatin is not well understood, but it appears that the cell has some control over whether cisplatin enters the cell. This suggests that cisplatin does not enter the cell by passive diffusion alone but that there is some active transport system involved. Furthermore, additional experiments have shown that decreased cellular accumulation of cisplatin is not due to increased efflux of cisplatin.1,3
- Sulfur-Containing Macromolecules Once inside the cell, cisplatin can interact with a variety of other molecules besides DNA—including two sulfur-containing macromolecules, metallothionein and glutathione, that sequester cisplatin and remove it from the cell. Metallothionein (MT) is believed to be involved with the detoxification of heavy metal ions in the cell. Production of MT is triggered by the presence of heavy metal ions, glucocorticoids (which are steroid hormones that promote the formation of both glucose from noncarbohydrate sources and glycogen, enhance the degradation of fat and protein, and enable animals to respond to stress), interferon (which is a signaling molecule in the immune system that greatly enhances antiviral responses), and stress. Both cisplatin and trans-DDP bind to MT, with 10 platinum atoms per molecule of MT. MT may contribute to cisplatin resistance, but the results are inconclusive. In some cases, the levels of MT are higher in cisplatin-resistant cells, but in other cases, the MT levels are unaffected.1,3 Like metallothionein, glutathione (GSH) is also involved in detoxification. GSH reacts with hydrogen peroxide and organic peroxides, the harmful byproducts of aerobic life. GSH is also essential for maintaining the normal structure of red blood cells.4 In the presence of cisplatin, GSH forms a 2:1 (GSH:platinum) complex that is then eliminated from the cell. Again, like MT, levels of GSH are increased in some—but not all—cisplatin-resistant cells, suggesting that there are other mechanisms of cellular resistance.3
- Increased DNA Repair Another way that cells can become resistant to cisplatin is to have an enhanced ability to remove cisplatin-DNA adducts and to repair cisplatin-induced lesions in DNA. Such an ability might result from the presence of certain DNA repair proteins. One example of a DNA repair protein that has been shown to repair cisplatin lesions is a nuclear protein called XPE-BF (xeroderma pigmentosum group E binding factor). Levels of XPE-BF were found to increase early in the development of cisplatin resistance. Another example of a DNA repair protein that may be involved in the recognition of cisplatin damage is ERCC1, most likely a DNA-binding protein. The gene encoding for ERCC1 is expressed at higher levels in cisplatin-resistant cells than in cells that are sensitive to cisplatin. Furthermore, in one case, a patient was treated with carboplatin, a close relative of cisplatin (see below); carboplatin was initially effective in treating the patient’s tumor, but resistance to this drug eventually occurred. As the tumor cells became resistant to carboplatin, the level of ERCC1 expression was found to increase.3
As with other mechanisms of cisplatin resistance, it appears that DNA repair is one of several possible mechanisms. Studies showing an increase in levels of DNA repair proteins as tumor cells become less sensitive—and therefore more resistant—to treatment with cisplatin have suggested that DNA repair seems to be the mechanism activated first in cisplatin resistance. As time goes on, other mechanisms, such as decreased intracellular accumulation and sequestration of cisplatin by sulfur-containing macromolecules, may also become significant.3
- Pil, P., Lippard, S. J. In Encyclopedia of Cancer, J. R. Bertino, Ed. Academic Press: San Diego, CA, 1997, Vol. 1, pp. 392-410.
- Zamble, D. B. Lippard, S. J. Trends in Biochemical Sciences, 1995, 20, pp. 435-439.
- Chu, G. Journal of Biological Chemistry,1994, 269, pp. 787-790.
- Stryer, L. Biochemistry, 4th ed. W. H. Freeman and Company: New York, 1995.