Methods of Treatment:
Cisplatin: The Platinum Standard
In 1965, Dr. Barnett Rosenberg, a professor of biophysics and chemistry at Michigan State University, became curious about the phenomenon of cell division. He had watched the process of cell division—called mitosis—with his own eyes through a microscope. The patterns in the movement of the cells as they divided and multiplied reminded Rosenberg of another natural phenomenon he had seen. This was the pattern of movements of tiny iron filings when they are scattered near a magnet. The iron filings move and wiggle as they settle into place within the electromagnetic field produced by the magnet. Rosenberg's curiosity was aroused by the similarity in the pattern of these two very different natural phenomena. He thought that perhaps there was some deep connection between the patterns. With his background in physics, Rosenberg knew that introducing an electrical current into the system could change the pattern that his familiar iron filings would take. He decided to conduct an experiment to see if the patterns of cell division depended upon electrical conditions as well.
Rosenberg's experiment was of a type that was very familiar to chemical scientists who had investigated the connections between electricity and chemistry—that is, the subject of "electrochemistry." One of the most basic electrochemical reactions is "electrolysis." In this an electrolysis reaction, a chemical current is passed through a substance, resulting in many different kinds of chemical changes. Most often, electrodes are placed at either side of a container of a chemical solution. The electrical current passes through the solution as it travels from electrode to electrode. Rosenberg created an electrolysis-type experiment in which he placed a platinum electrode at either side of a solution containing the E. coli bacteria. He was very particular in his choice of platinum electrodes, for platinum itself does not engage in many chemical reactions. This was important because Rosenberg wanted to investigate the effect of the electrical current alone upon the cell division process of the bacteria. He did not want the material that his electrodes were made out of to add any chemical changes of their own.
Rosenberg turned on the electric current and examined the bacteria. To his surprise, the bacteria were growing in length but failing to divide. After a few hours, cell division had ceased, but the elongation of the cells continued. To compound his surprise, Rosenberg noted that the cells did not begin to resume their process of division until some hours had passed after the electrical current had been turned off. He realized that the elongation of the cells meant that the growth processes of the cells were not affected, but that something had happened to interfere with the process of division. Since the effect lasted beyond the direct application of the electrical current, Rosenberg suspected that some electrochemical reaction was responsible for the disruption of the cell division rather than the electric current itself. He and his research group turned to unraveling this curious chemical puzzle.
After a great deal of further study, Rosenberg and his team determined that the electric current had prompted a chemical reaction between the normally unreactive platinum in the electrodes and certain nutrients in the solution containing the bacteria. In this reaction a new compound was produced. It was a molecule centered on a platinum atom called cis-diamminedichloroplatinum (II), or DDP.
Chemists had long known about this compound, known commonly as Peyrone's chloride, a name derived from the chemist who made it in 1845. DDP enjoyed renewed fame in the 1890s. In this decade, the chemist Alfred Werner published his pioneering work on the arrangements the atoms of a molecule in space. In particular, Werner studied compounds like DDP—inorganic compounds. He found that such compounds had one atom at the center with the other atoms arranged about it in simple geometric patterns. This work won Werner the Nobel Prize for Chemistry in 1913. These simple geometric patterns that Werner studied can be seen in the representations of DDP below.
The prefix "cis-" in cis-diamminedichloroplatinum refers to the arrangement of the atoms of this molecule around the central platinum atom (Pt). In this arrangement, both of the chlorine atoms (Cl) are on the same side of the platinum atom and both of the "groups" of nitrogen (N) and hydrogen (H) atoms (these nitrogen-hydrogen groups are molecules of ammonia) are on the opposite side. With the alternate arrangement of atoms around the central platinum atom, that is with an ammonia molecule and a chlorine atom on each of the two sides, a different prefix is used—"trans." This different arrangement is, then, "trans-diamminedichloroplatinum." Two different compounds like these with the same molecular formula but different molecular structures are called isomers.
Rosenberg reasoned that if the compound inhibited cell division, then it might be effective as an anticancer drug. Through the process of testing the compound as a drug, Rosenberg and his colleagues found very different properties of the two isomers of the compound. The trans isomer proved toxic to humans, but the cis isomer provided relief and inhibited several forms of cancer. It too had severe side effects, but much less severe than the trans isomer. Cisplatin, as Rosenberg dubbed cis-diamminedichloroplatinum, was approved for use as a cancer drug in 1978. Rosenberg was, however, not satisfied with the side effects caused by cisplatin. By 1985, Rosenberg had produced an analogue of cisplatin, called carboplatin, which had far fewer side effects. As the following structure shows, carboplatin has a complex of oxygen (O) and other atoms where the chlorine atoms were in cisplatin.
carboplatin
Both cisplatin and carboplatin currently are used to treat testicular and ovarian cancer. Cisplatin, like Gertrude Elion's 6-MP, is an example of an anticancer treatment that was discovered by serendipity, by following the curious puzzles that arise in scientific investigations.
For more information, at other Web sites...
The Nobel Prize in Chemistry 1913 — Information on the life and work of Nobel Prize winner Alfred Werner, from the Nobel Foundation.
Cisplatin: The Invention of an Anticancer Drug — a ChemCases case study from Kennesaw State University.
Cisplatin — A University of Bristol Molecule of the Month page, containing information on the history and chemistry of cisplatin, written by Mitch Miller.
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