From Basic Research to Cancer Drug: The Story of Cisplatin

if (n == null) The Scientist 13[14]:11, Jul. 05, 1999 News From Basic Research to Cancer Drug: The Story of Cisplatin By Ricki Lewis Clinical Trial Results for Treating Cervical Cancer The April 15, 1999 issue of The New England Journal of Medicine (NEJM) brought great satisfaction to Barnett Rosenberg, a retired Michigan State University biophysicist who founded the Barros Research Institute in Holt, Mich., in 1982.1,2,3,4 Not many scientists can watch basic research blossom into a cancer treatment that has extended or saved thousands of lives. Rosenberg's keen observation in 1961 led, 18 years later, to Food and Drug Administration (FDA) approval of cisplatin. The drug's conception, gestation, and birth illustrate the scientific process and also the importance of following even the strangest of hunches. Cisplatin revolutionized the treatment of testicular cancer, with success also against some ovarian and colon cancers. The trio of reports in the recent NEJM document remission in cervical cancer patients given cisplatin in combination with other treatments (See Box 1, in PDF file). "There had been no major changes in the cure rate of cervical cancer in 40 years. But we are gradually beginning to increase it with cisplatin and other mixtures of drugs. Cervical cancer is now approaching the situation with testicular cancer. We did it before, and it's likely we can do it again," says Rosenberg. The three studies plus two others in press show death rates slashed up to 50 percent. The findings were striking enough for the National Cancer Institute (NCI) to notify oncologists prior to publication, only the fifth time in history. "The results of the studies were so alike that I was absolutely astonished. I've never seen such similarity in scientific results in cancer research," Rosenberg adds. But the road to cisplatin was hardly smooth, and the tale offers a broader perspective of the challenges of basic research. I experienced a bit of what Rosenberg himself did, when as a fledgling writer still in grad school in 1979 I tried to interest magazine editors in an article on his work. I had heard Rosenberg give a seminar, and was intrigued by the serendipitous nature of the discovery. Alas, my article proposal brought an avalanche of rejection notes from editors, some mocking the very idea of using a heavy metal to treat cancer. When I told Rosenberg of the journalistic roadblock, he said wryly, "same experience I had." The story begins in 1961. Michigan State University in East Lansing had recruited Rosenberg from New York University to start a biophysics department, although he claims he had "no competence in biology--few physicists have."5 Looking for biologically oriented research questions, he decided to follow up on an observation. He had long wondered about the resemblance of iron filings clinging to a bar magnet, to the appearance of condensed chromosomes in a cell caught in the throes of binary fission. How might a magnet affect cells? Rosenberg decided to use an electromagnetic setup with platinum electrodes, a metal known to be inert. But before he added a continuous culture of mammalian cells whose chromosomes he wished to watch, he used E. coli to set the parameters of the experiment, turning on the electromagnet once the bacterial culture had reached a steady state. Soon after, the microbial population plummeted. Yet when he turned the electromagnet off, bacterial reproduction resumed. That in itself was interesting, but when Rosenberg examined the bacteria, he was startled--after exposure to the electromagnet, some had extended to 300 times their normal length! The cells had grown, but not divided. The implications were clear--Rosenberg had found something that blocks cell division, and such a something might counter the out-of-control cell cycle that is cancer. But it wasn't the electrical field that stopped the bacterial cells from dividing. After conferring with chemists, Rosenberg and his colleagues realized that a chemical reaction had occurred between the ammonium chloride used as an electrolyte and the platinum of the electrodes. The product: dichlorodiamineplatinum. It is part of the so-called scientific method to follow one experiment with others, as each triggers new questions, and the research now veered from biophysics to chemistry. Synthesizing the platinum compound and dumping it on bacteria did not have the anticipated effect of generating giants. But keen observational skills helped again. The researchers noted that dichlorodiamineplatinum left to sit on a shelf for a few weeks did have the desired effect of blocking bacterial cell division. The difference was that the compound on the shelf was exposed to light, and a photochemical reaction of some sort had taken place. The next clue was also confusing. The platinum compound synthesized in the lab had no effect on bacteria, but when collected from the electrodes, it squelched cell division. Chemistry once again explained both this effect and the photochemical influence. Dichlorodiamineplatinum exists as an isomer, the "trans" form having the two chlorines and two ammonias cattycorner in the molecule, and the "cis" form having them on the same side (See Box 2, in PDF file). Because the trans form is more stable, it predominates a synthesis reaction, but it was the elusive cis form that disrupts bacterial cell division--and only in large amounts. Photochemical reactions tend to favor formation of the isomer that is less likely to form in a synthesis reaction, and so exposure to ultraviolet wavelengths on the shelf converted trans molecules to cis. It was the excess of cis-dichlorodiamineplatinum--cisplatin--that halted bacterial cell division. A literature search revealed that the compound had been synthesized in 1848 and called "Peyrone's chloride," and again in 1890, when discovery of its isomerism started the field of coordination chemistry, Rosenberg relates. Plus, chemists had described antibacterial properties of platinum-group metals in 1953. Rosenberg's group and others further scrutinized the effects of various platinum group compounds on bacteria, amassing facts. Gram-negative bacteria were the most susceptible. Only a high concentration of the cis form of the compound stopped cell division. Treated cells recover, unlike their response to nitrogen mustard, which means that cisplatin does not squelch DNA synthesis. Most telling was the finding that cisplatin causes the phage lambda to become lytic (jump out of a host chromosome and begin replicating)--a characteristic of other anticancer compounds. In 1968 came crucial LD50 and tumor-shrinkage tests in mice in the Michigan State lab. In the protocol, repeated many times, mice received transplants of a standard sarcoma on day zero, cisplatin or placebo on day one, and then were sacrificed on day eight. Results were so amazing that Rosenberg notified the NCI immediately. He was invited to give a talk at the agency, which he recalls was met with "perceptible but understandable coolness." But he left several samples of cisplatin for government researchers to incorporate into their drug screening program, and they tried it on mice with leukemia. Not only did it work on this second type of cancer, but tweaking the protocol to give the drug on day eight instead raised the success rate in shrinking tumors to near 100 percent. Rosenberg submitted a grant to NCI that was, not surprisingly, funded, and in 1969, Nature published the first report on cisplatin's anticancer activity.6 "An American journal of almost equal distinction turned it down," recalls Rosenberg, because a referee claimed that it was hardly noteworthy among the many potential cancer drugs being described. Perhaps the lack of attention in some circles was a sign of the times, before Richard M. Nixon officially declared the "war on cancer" in 1973. But when professor Sir Alexander Haddow, then head of the Chester Beatty Institute in London, showed that cisplatin was active against melanoma in mice, more people took notice. Tests continued in dogs and monkeys to determine doses and toxicities. Molecular studies revealed that the cis compound crosslinks DNA that is rich in quanine and cytosine, both within and between strands. In 1972 clinical trials began on cancer patients who had exhausted all treatments, to establish doses and side effects. Surprisingly, for there isn't much hope in such investigations, 20 percent of the participants had partial or complete remissions for varying times. But kidney toxicity was emerging as a hurdle, causing one reviewer to comment, "This is too interesting a drug to drop, but too dangerous for extensive use." Phase II clinical trials evaluated patients at earlier stages of disease, in a crossover design where the patient received cisplatin only if another drug failed. Meanwhile, animal studies revealed synergies of cisplatin with other drugs and radiation, effects echoed in the 1999 reports with cervical cancer. (Cisplatin apparently inhibits repair of radiation-induced damage circuitously--it shrinks the tumor, which allows more oxygen to reach the cells, and they resume the cell cycle, becoming more sensitive to the radiation.) A key pilot study at the Roswell Park Memorial Institute in Buffalo, N.Y., was critical to the drug's approval in 1979--13 of 15 men with testicular cancer responded, seven completely, for long time periods. Bristol Laboratories in Syracuse, N.Y., began producing the drug, which was added to protocols to treat cancers of the testes, ovaries, and bladder. An analog with carbons replacing the platinums, called carboplatin, soon followed. Cisplatin went on to become a top-selling cancer drug, but again the road was rocky, this time because of patient backlash. "Cisplatin had terrible side effects. The kidney toxicity almost killed the drug, and it caused such severe nausea and vomiting that people refused to take it. But now a very good drug stops the nausea and vomiting, and hydration takes care of the kidney toxicity. And carboplatin has fewer side effects," Rosenberg says. But with the recent reports, the long history of success in treating certain cancers, and more than a dozen clinical trials ongoing to explore new indications, the story of cisplatin isn't over. Science never is. Ricki Lewis (rickilewis@nasw.org) is a contributing editor for The Scientist. 1. M. Morris et al., "Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer," The New England Journal of Medicine, 340:1137-43, April 15, 1999. P.G. Rose et al., "Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer," The New England Journal of Medicine, 340:1144-53, April 15, 1999. H.M. Keys et al., "Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma," The New England Journal of Medicine, 340:1154-61, April 15, 1999. G.M. Thomas, "Improved treatment for cervical cancer--concurrent chemotherapy and radiotherapy," The New England Journal of Medicine, 340:1198-1200, April 15, 1999. B. Rosenberg, "Platinum complexes for the treatment of cancer," Interdisciplinary Science Reviews, 3:134-47, 1978. B. Rosenberg et al., "Platinum compounds: a new class of potent antitumor agents," Nature, 222:385-6, 1969.

From Basic Research to Cancer Drug: The Story of Cisplatin

From Basic Research to Cancer Drug: The Story of Cisplatin

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