17. Drug Resistance

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 

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
(1) Pil, P., Lippard, S. J. In Encyclopedia of Cancer, J. R. Bertino, Ed. Academic Press: San Diego, CA, 1997, Vol. 1, pp. 392-410.

(2) Zamble, D. B. Lippard, S. J. Trends in Biochemical Sciences, 1995, 20, pp. 435-439.

(3) Chu, G. Journal of Biological Chemistry,1994, 269, pp. 787-790.

(4) Stryer, L. Biochemistry, 4th ed. W. H. Freeman and Company: New York, 1995.

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Case Study in Cisplatin

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