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Typical Anticancer


For cisplatin, the "penicillin of cancer drugs" is perhaps a proper moniker because it has been one of the most widely prescribed as well as a first and effective treatment for many cancer diagnoses. Unlike many cancer drugs, which are organic molecules with complex structures, cisplatin is an inorganic molecule with a simple structure. In designing and evaluating new cancer treatments, researchers use cisplatin as the gold standard against which new medicines are compared. This drug is probably most widely known for its prominent role in helping Tour de France winner Lance Armstrong fight testicular cancer.

Marketed as Platinol, cisplatin interferes with the growth of cancer cells, slowing their advance in the body. Cisplatin is used to treat many types of cancer, but it is most widely prescribed for testicular, ovarian, bladder, lung, and stomach cancers.

Human trials produced positive results, but the drug's benefits initially were hampered by toxic side effects, such as joint pain, ringing in the ears, trouble in hearing, and weakness. Once the side effects were made bearable through the use of auxiliary therapies, the compound's effectiveness was proven, and it was approved for use in the U.S. by the Food & Drug Administration in 1978.

BLOCKED An HMG-domain protein (HMGB1; domain A shown as gray ribbon) inserts a phenyl group (yellow) into the groove created when cisplatin (platinum shown in red) forms a complex with DNA, causing it to bend. IMAGE BY MIKE MCCORMICK

BLOCKED An HMG-domain protein (HMGB1; domain A shown as gray ribbon) inserts a phenyl group (yellow) into the groove created when cisplatin (platinum shown in red) forms a complex with DNA, causing it to bend.

FIRST SYNTHESIZED by Michel Peyrone in 1845, cisplatin is historically known as Peyrone's chloride. The structure was first elucidated by Alfred Werner in 1893. The compound then experienced decades of relative obscurity.

All that changed in the early 1960s when Barnett Rosenberg, a professor of biophysics and chemistry at Michigan State University, began a series of experiments to measure the effect of electrical currents on bacterial cell growth. His research yielded Escherichia coli that were 300 times the normal length. The treatment had only prevented cell division--not other growth processes--which led to the elongation. The researchers were able to deduce that this effect was due not to the electrical fields, but to a compound that was formed in a reaction between the "inert" platinum electrodes and components of the solution containing the bacteria. The compound was later determined to be cisplatin.

The compound's effect of preventing cell division prompted Rosenberg's group to test cisplatin against tumors in mice (Nature 1965, 205, 698); the compound was found to be highly effective and entered into clinical trials in 1971. Cisplatin was licensed exclusively to Bristol-Myers Squibb in 1977.

When confronted with interesting research results, Rosenberg not only decided to pursue them vigorously, he sought the help of other scientists not directly related to his primary field. He enlisted the help and expertise of researchers trained in microbiology, inorganic chemistry, molecular biology, biochemistry, biophysics, physiology, and pharmacology. This multidisciplinary approach was the key to capitalizing on his serendipitous finding.

Although the mechanism has not yet been fully elucidated, cisplatin is generally believed to kill cancer cells by binding to DNA and interfering with the cell's repair mechanism, which eventually leads to cell death. But not every platinated complex interacting with DNA unequivocally causes cytotoxicity. For example, the trans isomer of cisplatin is not an effective chemotherapeutic agent. The different geometries of these two isomers result in different binding modes with DNA.

Inside a cell, cisplatin undergoes hydrolysis, producing the highly reactive charged platinum complex [Pt(NH3)2ClH2O]+. This complex coordinates to DNA through the N7 atom of either a guanine or adenine base. Further hydrolysis displaces the remaining chloride ligand, and the platinum can bind to a second nucleotide base. The cisplatin-DNA adduct is recognized by a high mobility group (HMG)-domain protein--among other DNA repair proteins--which binds tightly to the complex. The adduct causes destacking of the nucleotide bases, resulting in the DNA helix becoming kinked. In this way, cisplatin can be thought of as a monkey wrench in the DNA excision repair system.

Although cisplatin is an effective drug, researchers have sought second-generation compounds that have lower therapeutic doses and fewer side effects. The most common is carboplatin, which entered the U.S. market as paraplatin in 1989 for initial treatment of advanced ovarian cancer and now outranks cisplatin in sales. Paraplatin, or cis-diammine(1,1-cyclobutanedicarboxylato)platinum (II), owes its lower toxicity to the dicarboxylate ligand, which slows down the degradation of carboplatin into potentially toxic derivatives. Other analogs include ammine platinum(IV) dicarboxylates, which are metabolized to form platinum(II) cisplatin analogs.—STEPHEN TRZASKA


The Top Pharmaceuticals
That Changed The World
Vol. 83, Issue 25 (6/20/05)
Table Of Contents


Cisplatin structure


  • (SP-4-2)-Diamminedichloroplatinum

CAS Registry

  • 15663-27-1

Other Names

  • cis-Diamminedichloroplatinum
  • Platinol-AQ
  • cis-platinum(II)
  • cis-DDP


1978, Bristol-Myers Squibb; latest analog is carboplatin, marketed as Paraplatin


  • Global (for Paraplatin) $673 million (2004), $905 million (2003)

Did you know that cisplatin and its analogs are the only inorganic complexes currently used in cancer therapy?