11. Cisplatin as an Anticancer Drug
NEWS: June 22, 2005 Cisplatin and Lung Cancer: Cisplatin chemotherapy now recognized for dramatic lengthening of survival for some common types of lung cancer. Read through this unit for a description of cisplatin science
went from a disease that normally killed about 80% of the patients, to one which is
to 95% curable. This is probably the most exciting development in the
treatment of cancers that we have had in the past 20 years. It is now the treatment of
first choice in ovarian, bladder, and osteogenic sarcoma [bone] cancers as well."
Barnett Rosenberg, who led the research group that discovered cisplatin, commenting on the impact of cisplatin in cancer chemotherapy1
The success of cis-diamminedichloroplatinum(II), or cisplatin, in curing tumors in mice, along with the toxicity information gained from studies on dogs and monkeys, suggested that this compound might be effective as an antitumor agent in people with cancer. Before any new drug candidate can be approved for use in the United States, it must undergo extensive testingin several phasesaccording to the guidelines set by the Food and Drug Administration (see module on the FDA drug approval process). In the first phase of clinical trials, a new potential anticancer drug is tested on terminally ill patients with cancer who no longer respond to current therapies. After these people have signed an informed consent agreement, they may be treated with new drugs. Unfortunately, the majority of these people are not cured of cancer. At this stage, they are already very ill, and their strength has been sapped by the disease and by other treatments they may have received. However, people who participate in phase I clinical trials serve an invaluable service in that they provide information about side effects and appropriate dosage levels and schedules. For example, it was at this point in cisplatin studies that researchers became aware of the side effect of hearing losssomething that could not have easily been determined from animal studies (see module on toxic side effects).2Despite the poor prognosis for many cancer patients at this stage, some patients did benefit from treatment with cisplatin: roughly 20% of the patients experienced partial or complete remissions. In particular, cisplatin produced responses in approximately 80% of patients with testicular cancers, greater than 90% of patients with ovarian carcinomas, roughly 40% of patients with head and neck cancers, and also around 40% of patients with some lymphomas. Sadly, colon carcinoma, a type of cancer that is very resistant to drugs, did not respond to cisplatin at all. The success of cisplatin in treating a fairly wide variety of cancers, however, showed the promise of this new drug. Later, as one clinician put it, " . . . [cisplatin] appears to be too good a therapeutic agent to abandon, yet too toxic for general use."2 This clinician was referring to newly discovered kidney toxicity, for which treatments have now been developed, as described in the module on toxic side effects. In the second phase of clinical trials, cisplatin was used in a crossover pattern with other anticancer drugs to treat recently diagnosed cancer patients. A patient was first treated with one drug, and if s/he did not respond to that drug, s/he was treated with a second drug and vice versa. Cisplatin produced higher response rates in phase II clinical trials than it did in phase I, a fairly common result.
In fact, combination therapies to treat cancer are quite common. The hope is that the drugs will work together, producing a synergisticor at least an additiveeffect to cure the cancer, while not producing an additive effect for dose limiting side effects. Cisplatin is often used in combination with one, two, three, or even four other drugs, with good results. One striking example of this is the combination of cisplatin with 5-fluorouracil to treat terminally ill colon carcinoma patients. In a study done at the University of Wisconsin, the tumors in three of nine such patients decreased in size by more than 50% for varying lengths of time. This was an encouraging result, particularly since cisplatin alone showed no effect on colon cancers in phase I clinical trials.2Following the encouraging results of these studies, cisplatin was approved by the Food and Drug Administration at the end of 1978 for the treatment of genitourinary tumors. Today it is one of the most widely used and successful drugs for the treatment of cancer.3
(1) Kotz, J. C., Paul Treichel, J. Chemistry and Chemical Reactivity, 4th ed. Saunders College Publishing: Philadelphia, 1999. (2) Rosenberg, B. In Nucleic Acid-Metal Ion Interactions, T. G. Spiro, Ed. John Wiley & Sons, Inc.: New York, 1980, Vol. 1, pp. 1-29. (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.
Concept Map for this ChemCase
Concept Map for this ChemCase
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