Platinum as an Anticancer Drug
From Chempedia
Platinum as an Anticancer Drug
When most people hear the word platinum, they think of a precious metal used for jewelry. What many people do not know is that platinum is very useful as a treatment for several types of cancer, such as ovarian, testicular and cervical. Platinum’s use as a cancer treatment was discovered accidentally by Dr. Barnett Rosenberg, while conducting an experiment to determine the effects of an electrical current on cell division.
Dr. Rosenberg used platinum electrodes to run a current through a solution containing E. coli. He discovered that something had caused cell division to cease but did not affect the growth of the cell. After further research, he determined that the cell division was arrested by a molecule produced after a current was passed through the solution via platinum electrodes. That molecule, which contained platinum, is known as cis-damminedichloroplatinum (II), DDP or cisplatin. Further, Dr. Rosenberg found an isomer, trans-damminedichloroplatinum (II), that also arrested cell division, but it proved toxic to humans. After DDP was discovered to stop cell division, it became immediately recognized for its effectiveness as a cancer treatment, despite its side effects, which include nausea and vomiting. Although thousands of platinum compounds are now being synthesized, only cisplatin, carboplatin, and oxaliplatin are used clinically in the United States.
Cisplatin is the most widely used platinum-based molecule. It has a molecular formula of Cl2H6N2Pt and a molecular weight of 300.1 grams per mole. Deep yellow in color when in the form of a crystalline solid and clear in solution, cisplatin\’s melting point is 270 degrees Celsius. The name which it is commonly marketed by is Platinol©.
Figure 1.Molecular shape of cisplatin and its toxic isomer, transDDP1
Administered to a patient through an intravenous solution of sodium chloride, cisplatin manages to stay intact in the bloodstream because of high concentrations of chloride ions. Cisplatin enters a cell through diffusion or through active uptake by proteins lodged in the cell membrane. Once a cisplatin molecule enters the cell, it undergoes hydrolysis, which is the process of cleaving a molecule by reaction with water. In this process, part of the molecule bonds to the water. In the case of cisplatin, a chlorine atom is replaced with a water molecule, which creates a positively charged molecule. Hydrolysis takes place in the cell, where there is a lower concentration of chloride ions and a higher concentration of water.
Once a cisplatin molecule is in a cell and hydrolysis has occurred, it has multiple targets. It can affect DNA, RNA, and mitochondria. However, DNA is its primary biological target. Cisplatin affects DNA mainly by forming certain adducts using covalent bonding to nitrogen atoms of the DNA nucleotides, particularly the N7 positions of purine bases. The most important adduct is where the chlorine atoms are replaced by the nitrogen atoms on adjacent nucleotides of the same strand of DNA. The most common purine bases involved are usually guanines, although some guanine and adenine are also present. Formation of the cisplatin on the DNA causes the purine bases to become misaligned, and consequently the DNA helix becomes kinked.
Cisplatin binds to the DNA, but what actually causes cell death is more complicated. Research has shown that the binding of cisplatin to DNA affects the replication, transcription and repair of DNA. The binding of cisplatin to DNA blocks the action of polymerase, an enzyme essential to DNA synthesis. Therefore, the cell cannot replicate.
Figure 2. (A) The structure of cisplatin attached to DNA. The misaligning of nitrogen bases is visible. (B) Cisplatin bonded to two guanines in a DNA adduct.1
Figure 3. Formation and effects of cisplatin adducts. The platinum atom of cisplatin binds covalently to the N7 position of the DNA. Cisplatin–DNA adducts cause various cellular responses, such as replication arrest, transcription inhibition, cell-cycle arrest, DNA repair and apoptosis.2
In addition, the cisplatin-DNA adduct exposes a groove surface where high mobility groups (HMG) and other DNA repair proteins bind. HMG’s are identical sequences of amino acids which produce proteins. These proteins become irreversibly bound to the cisplatin-DNA adduct which distort the DNA’s shape. The distortion inhibits effective repair of the DNA, and eventually cell death occurs.
Numerous studies of platinum-based anti-cancer drugs in recent years have furthered our understanding of how the drugs affect DNA, how cell cycles arrest, and how DNA repair begins. Such studies provide researchers with a fundamental basis by which they can develop better platinum-based chemotherapeutic molecules. New platinum-based drugs formed in research laboratories might someday prove useful in a clinical setting.
One molecule proven very successful is carboplatin, which works almost the same as cisplatin, attaching to DNA in the same manner. The main difference is that carboplatin has far fewer side effects, and has often worked in cases in which cisplatin failed. Due to the commitment of the pharmaceutical industry, it is likely that future studies will determine more efficient platinum-based drugs.
Figure 4. New platinum based molecules that are being used to treat cancer.1
Researched and written by: Scott Thomas Murphy and Gunnar Nelson
Footnotes
References
1.Kennesaw State University, Chemcases.com. http://science.kennesaw.edu/~mhermes/cisplat/ (accessed October 2005)
2.Wang, doug; Lippard, Steven J.; Nature Reviews Drug Discovery 4, 2005, 307-320. Hess, Suzanne M.; Mounce, Amanda M.; Sequeira, Russel C.; Augustus, Todd M.\’ Ackley, Margaret C.; Bierbach, Ulrich. Cancer Chemotherapy Pharmacology. 2005, 56: 337-343
3.Ang, Wee Ang; Khalailia, Isam; Allardyce, Claire S.; Juillerat-Jeanneret, Lucienne; Dyson, Paul J. J. AM. CHEM. SOC. 2005,127, 1382-1383
4.Magic Bullets Chemistry vs. Cancer, The Chemical Heritage foundation, 2001. http://www.chemhertage.org/Educationalservices/pharm/chem/readings/cisplat.htm (accessed October 2005)
5.Cisplatin. Miller, Mitch, Netgenics Inc. http://www.chm.bris.ac.uk/motm/cisplatin/htmlonly/ (accessed October 2005)
