How does chemotherapy actually work: Mustard, Platinum and Alkyl groups

There are two main forms of cancer treatments. The more traditional chemotherapeutic agents are cytotoxic, meaning that they kill rapidly proliferating cells. Newer drugs are referred to as targeted therapy, since they are able to discriminate between healthy cells and the mutated cells which form the tumor.

Within each group, there are various forms that chemotherapeutic agents can take. Alkylating agents, antimetabolites, anti-microtulule agents tppisomerase inhibitors and cytotoxic antibiotics are a few of the discovered therapies.

Alkylating agents: Nitrogen mustard & Cisplatin   

As discussed on a previous post, these are derived from mustard gas used in WWI. Their ability to add alkyl groups to many molecules such as DNA and RNA and other proteins makes them invaluable for treating cancer.

How do they work? When used as a chemotherapeutic agent, The alkyl groups (CH2) on the nitrogen mustard binds covalently to DNA, either binding twice to one strand (called intrastrand crosslink), or it will bind to both strands (interstrand crosslink). If you imagine DNA as a zip on a jacket, then the mode of action of nitrogen mustard is analogous to either sticking a lump of blue-tack onto one strand of your zip, or gluing one section of both strands together. Either way, you won’t be able to do up your jacket. When the cell attempts to replicate this section of DNA, the nitrogen mustard thwarts all efforts. Eventually, when the cell detects this damage, it tries to repair the DNA. This causes the strands to break, and since the body likes to keep itself incredibly pristine, then enzymes rush in to rid the body of a faulty cell, thus leading to apoptosis (cell death).

Nitrogen mustard works in this way, and can bind to any of the atoms present in DNA. However, it has a preference to one of the Nitrogen atoms on the base guanine, which is a key component of DNA.

 

Cisplatin has the same mode of action, but has a different structure to nitrogen mustard. Just as nitrogen mustard has an amazingly serendipitous story to explain its discovery, cisplatin’s origins are just as miraculous:

“An “accidental” discovery leads to cisplatin. Because platinum was thought to have no biological activity, Dr. Rosenberg and his colleagues put platinum electrodes into a solution containing the common laboratory bacteria E. coli and turned on the power. As soon as the current started, the bacterial cells stopped dividing, although they kept growing to up to 300 times their normal length. When the power was cut off, the bacterial cells began dividing again. It appeared that the electrical field was controlling cell division. Dr. Rosenberg later called this experiment the “accidental discovery that led eventually to cisplatin.”

However, Dr. Rosenberg and his colleagues did not yet know what they had discovered. They thought they might have found a way to control cell growth with electrical currents. They spent two years trying to discover why the electrical field had such a profound effect. Finally, they realized that electricity had nothing to do with it. Cell division was being blocked not by the electric field, but by a platinum compound released from the electrodes. After another two years, Dr. Rosenberg’s team identified the compound that affected cell division so dramatically. It was later named cisplatin.

Researchers use cisplatin to control cancer cell division and expansion. Dr. Rosenberg then wondered whether cisplatin would also block cell division in tumors. Testing it in asarcoma mouse model, he and his colleagues found that it did indeed attack tumors. While cisplatin was highly toxic—for example, causing kidney damage when used at a high dose—the mice were able to tolerate the drug in low doses. More importantly, the tumors responded to cisplatin and shrank. Six months later, the mice remained healthy and showed no return of the tumors.”

http://www.cancer.gov/research/progress/discovery/cisplatin

Cisplatin is a molecule containing a platinum ion in the centre of a square; two chloride ions and two ammonia ions form the corners of this square. So what happens when cisplatin gets into the body? Since it is neutrally charged, it can cross the cell membrane. On entering the cell, one of its chlorides is replaced by a water molecule. When coming into contact with DNA, since the water is loosely attached to the cisplatin, a nitrogen atom on the guanine base easily displaces the water. 

As a result, the platinum molecule ends up attached to the DNA by a dative covalent bond, preventing cell division. Thus, the cells can no longer sustain its rapid division and the tumour begins to shrink. This platinum causes a ‘kink’ in DNA. Normally, enzymes which regulate and methodically check all DNA are able to repair damaged areas. However, since this kink is unrecognisable to the enzymes, they become ‘confused’ and instead initiate apoptosis.

http://www.rsc.org/chemistryworld/podcast/CIIEcompounds/transcripts/cisplatin.asp

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