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CisplatinCisplatin was the first available platinum-based anticancer drug used to treat various types of cancers, including sarcomas and small cell lung cancer. It can be rightfully regarded as a coordination chemists' dream come true, in finding itself an application to treat various forms of cancers. The discovery has since created different derivatives, most notably the widely-used carboplatin, which is also beleived to function like cisplatin itself underin vitro conditions. One of the key reasons for its cytotoxic activity is believed to be its ability to form irreversible intrastrand crosslinks with guanine bases (predominantly) thereby producing 'kinks' in DNA structure to allow any meaningful biologial activity. Thus the subsequent effects are believed to be the halt in DNA replication, and a host of other activities that result in stopping the uncontrolled cellular divisions seen in malignant cells. However, the drug is indiscriminate to other cells in the body, and thus creates serious side effects. History Cisplatin, first isolated as Peyrones Chloride known chemically as cis-diaminedichloroplatinum(II) (CDDP) in the late 19th century, has proven to be a potent anticancer drug. After its serendipitous discovery in the 1960s by Prof Rosenberg and his co workers while carrying out experiments concerning the mitotic division of Escherichia coli (E. coli) in electrical fields, it spurred curiosity throughout the scientific community. In the 1970s, a series of experiments were conducted at the University of Michigan State to test the effects the cis-diaminedichloroplatinum(II), along with other platinum coordinate complexes, on sarcomas artificially implanted in rats. This study found that cis-diaminedichloroplatinum(II) was the most effective out of this group, which started the medicinal career of cisplatin. Approved for clinical by the American Food and Drug Administration (FDA) in the 1970s, it revolutionized the treatment of cancer. Detailed studies on its molecular mechanism of action, using a variety of spectrocopic methods including X-ray, NMR and other physico-chemical methods, revealed its ability to form irreversible crosslinks with bases in DNA. Most notable among these is the intrastrand GpG adducts which form nearly 90% of the adducts. This is besides other equally important adducts like inter-strand crosslinks and monfunctional adducts that have been postulated to contribute to its activity. All said and done, the dust yet to settle on the mechanism of action of this deceptively simple looking drug. Physiological Effects of Cisplatin Introduced to clinical use in 1979, cisplatin has been saving lives since then by effectively destroying tumours and other cancerous growths. However, it has not been the magical panacea to cancer as hoped. Underlying cisplatins incredible curative properties, there are many shortcomings and side effects. At the onset of using cisplatin, the cancer seems to disappear rapidly, and may cause remission of the cancer. This period of remission is usually short-lived, however, as the cancer often returns after the halting of cisplatin treatments. Along side its positive effects; there is also a long list of debilitating side effects. Nephrotoxicity, or poisoning of the kidneys, is a major concern when cisplatin is prescribed as a chemotherapy agent. Due to the high reactivity of cisplatin and the chemical nature of transition metals in general, it is highly incompatible with the inner environment of the body. In an effort to rid of these substances, the kidneys are effectively working overtime, strenuously trying to excrete the cisplatin, or anything that the cisplatin may have reacted with (primarily sulphur-containing proteins in the bloodstream). This over-activity and overexposure of the kidneys to cisplatin and cisplatin complexes causes degradation of the renal cells, and eventually leads to renal failure. This is combated by using diuretics and infusing copious amounts of fluid into the patient, in an attempt to dilute these toxins sufficiently to prevent permanent kidney failure. There are other, less debilitating, side effects, including hair loss, nausea and vomiting, and ototoxicity (hearing loss). This is due to the lack of cell-specificity in cisplatin; they cannot discriminate between a cancerous cell and a normal somatic cell. Cisplatin functions mostly as a quick killer of cells that divide very rapidly, because of the increased rate of DNA replication. As it was stated before, the presence of the ternary complex prevents mitosis, and triggers programmed cell death. But many other normally functioning cells that undergo frequent divisions (namely the cells of the hair follicles and the cells that line the digestive tract) are also under attack from the cisplatin, and hence they too are killed. Although no permanent damage is done (the sheer number of these cells in the body and the capability for other cells to compensate), the killing of these cells produces the unpleasant side effects. References - Barefoot, R. R. Speciation of platinum compounds: a review of recent applications in studies of platinum anticancer drugs. Journal of Chromatography B: Biomedical Science and Applications. Volume: 751, Issue: 2, February 25, 2001, pp. 205-211.
- Lockich, Anderson. Carboplatin versus cisplatin in solid tumors: An analysis of literature. Annals of Oncology. Volume: 9, Issue: 1, January 1998, pp. 13-21.
- A comparison of the genotoxic effects of carboplatin and cisplatin in Escherichia Coli. Mutation Research/DNA Repair. Volume: 362, Issue: 3, April 2, 1996, pp. 249-259.
- Smith, Andri. Cisplatin: The Invention of an Anticancer Drug. http://chemcases.com/cisplat/index.htm
- MedlinePlus link to information on drug-facts Cisplatin
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