Researchers at Massachusetts Institute of Technology (MIT) in the US who are testing phenanthriplatin, a new experimental drug based on platinum, say it kills cancer cells better and may provide a more effective alternative to cisplatin, the most commonly used approved platinum chemotherapy drug.
Platinum-based chemotherapy drugs are among the most powerful and widely used against cancer. However, they have toxic side effects, and tumors can become resistant to them.
Cisplatin, the most common platinum chemotherapy drug, was first approved in the US in 1978. It is particularly effective against testicular cancer, and is also used in the treatment of ovarian and some lung cancers, as well as lymphoma and other cancers.
In a paper published in the Proceedings of the National Academy of Sciences (PNAS), senior author Stephen J Lippard and colleagues suggest phenanthriplatin not only kills cancer cells better than cisplatin, but it may also evade cancer-cell resistance to conventional platinum-based drugs.
Lippard, a professor of chemisty, has been studying platinum drugs for a long time. He told the press he had long believed platinum was special in its ability to deal with cancer. Now, using new variants, “we might have a chance of applying platinum to a broader range of cancer types, more successfully,” he said.
One reason that phenanthriplatin appears to be more effective than cisplatin is that it can get into cancer cells more easily. Another reason is that it inhibits transcription, the first step of gene expression, where cells convert DNA to RNA.
Platinum-based drugs are effective against cancer because at their centre is a platinum atom joined to two ammonion molecules and two chloride ions. The compound is negatively charged, but when it enters the cancer cell it becomes positively charged because the chloride ions are replaced by water molecules.
The water molecules are easily displaced, allowing the platinum-based compound to attach to DNA in the cancer cell: it forms cross-links in the DNA that block the cell’s ability to read the code, which is essential for cell function. If enough of the DNA is unreadable, the cell dies. This is how cisplatin works.
At first, it was thought that only compounds with two DNA binding sites (the two chlorine ions that are replaced by water) would be effective against cancer cells, because it was the ability to form cross links that mattered. But around the 1980s, scientists began to discover some positively-charged platinum compounds that can only bind to DNA at one site also have anti-cancer properties, and so they became interesting again.
For some time, Lippard and his group have been experimenting with different platinum compounds and looking at this underlying mechanism. They want to find similar drugs that could be more powerful, work against more types of cancer, plus have fewer side effects and evade cancer-cell resistance.
In 2008, they looked at pyriplatin, which is similar to cisplatin, except one of the chlorine atoms is replaced by a six-membered pyridine ring containing five carbon atoms and one nitrogen atom. But when they tested it, it was not as powerful in killing cancer cells as as cisplatin or oxaliplatin, another FDA-approved platinum-based cancer drug.
But it got them thinking, and they set off looking for similar compounds with larger rings; plus they had a hunch larger rings would make the drug more effective at blocking DNA transcription. And that’s how they came across phenanthriplatin.
In tests using 60 types of cancer cell, phenanthriplatin was between 4 and 40 times more powerful than cisplatin, depending on the cancer type. And, due its different pattern of activity, the researchers suggest it could be effective against cancer types that cisplatin is no good for.
When faced with cisplatin, some cancer cells are able to establish defences and develop resistance to the drug. The cells contain sulfur compounds such as glutathione that attack the platinum and destroy it before it can reach and bind to DNA.
The researchers found phenanthriplatin appears to evade some of these defences because its bulky three-ring attachment seems to stop the sulfur from mounting such a powerful attack on the platinum.
“… it may avoid cytoplasmic platinum scavengers with sulfur-donor ligands that convey drug resistance,” they write.
Luigi Marzilli, a professor of chemistry at Louisiana State University, was not involved in the study. He said phenanthriplatin shows promise as a new cancer treatment because:
“It expands the utility of platinum drugs and avoids some of the problems that existing drugs have.”
Lippard and colleagues are now doing animal tests to find out how the drug spreads in the body and how well it kills tumors in the body as opposed to cells in a test tube. Lippard says they may be able to modify the compound to improve those properties.
Written by Catharine Paddock PhD