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Cisplatin
Systematic (IUPAC) name
cis-diamminedichloridoplatinum(II)
Identifiers
CAS number15663-27-1
ATC codeL01XA01
PubChem84691
DrugBankAPRD00359
Chemical data
FormulaH6Cl2N2Pt 
Mol. mass300. IUPAC Nomenclature is a system of naming Chemical compounds and of describing the science of Chemistry in general CAS registry numbers are unique numerical identifiers for Chemical compounds Polymers biological sequences mixtures and Alloys They are also referred to The Anatomical Therapeutic Chemical Classification System is used for the classification of drugs It is controlled by the WHO Collaborating Centre for Drug A section of the Anatomical Therapeutic Chemical Classification System. PubChem is a Database of chemical Molecules The system is maintained by the National Center for Biotechnology Information (NCBI a component The DrugBank database available at the University of Alberta is a unique Bioinformatics and Cheminformatics resource that combines detailed drug (i A chemical formula is a way of expressing information about the Atoms that constitute a particular Chemical compound, and how the relationship between those atoms changes Hydrogen (ˈhaɪdrədʒən is the Chemical element with Atomic number 1 Chlorine (ˈklɔriːn from the Greek word 'χλωρóς' ( khlôros, meaning 'pale green' is the Chemical element with Atomic number 17 and Nitrogen (ˈnaɪtɹəʤɪn is a Chemical element that has the symbol N and Atomic number 7 and Atomic weight 14 Platinum (ˈplætɪnəm is a Chemical element with the Atomic symbol Pt and an Atomic number of 78 The molecular mass (abbreviated m of a substance, more commonly referred to as molecular weight and abbreviated as MW, is the Mass of one 05 g/mol
Pharmacokinetic data
Bioavailabilitycomplete
Protein binding> 90%
Metabolism ?
Half life30-100 hours
ExcretionRenal
Therapeutic considerations
Pregnancy cat.

D(US)

Legal status
RoutesIntravenous

Cisplatin, cisplatinum or cis-diamminedichloridoplatinum(II) (CDDP) is a platinum-based chemotherapy drug used to treat various types of cancers, including sarcomas, some carcinomas (e. In Pharmacology, bioavailability is used to describe the fraction of an administered Dose of unchanged drug that reaches the Systemic circulation, one of A drug's efficiency may be affected by the degree to which it binds to the proteins within Blood plasma. Drug metabolism is the Metabolism of drugs, their Biochemical modification or degradation usually through specialized enzymatic systems The biological half-life of a substance is the time it takes for a substance (drug radioactive nuclide or other to lose half of its pharmacologic physiologic or radiologic activity Excretion is the process of eliminating waste products of Metabolism and other non-useful materials The pregnancy category of a pharmaceutical agent is an assessment of the risk of fetal injury due to the pharmaceutical if it is used as directed by the mother during The United States of America —commonly referred to as the The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction In Pharmacology and Toxicology, a route Platinum (ˈplætɪnəm is a Chemical element with the Atomic symbol Pt and an Atomic number of 78 Chemotherapy, in its most general sense refers to treatment of disease by chemicals that kill cells specifically those of micro-organisms or Cancer. Medication, also referred to as medicine, can be loosely defined as any substance intended for use in the diagnosis cure mitigation treatment or prevention of disease A sarcoma (from the Greek 'sarx' meaning "flesh" is a Cancer of the connective or supportive tissue ( Bone, Cartilage, Fat A carcinoma is any Malignant Cancer that arises from epithelial cells. g. small cell lung cancer, and ovarian cancer), lymphomas and germ cell tumors. Lung cancer is a Disease of uncontrolled Cell growth in tissues of the Lung. Ovarian cancer is a cancerous growth arising from an Ovary. The cancer most commonly forms in the lining of the ovary (resulting in epithelial Lymphoma a type of Neoplasm that originates in Lymphocytes (a type of White blood cell in the vertebrate Immune system) It was the first member of its class, which now also includes carboplatin and oxaliplatin. CARBOplatin is a Chemotherapy drug used against some forms of Cancer (mainly ovarian carcinoma lung head and neck cancers Oxaliplatin is a Platinum -based Chemotherapy drug in the same family as Cisplatin and Carboplatin. Platinum complexes are formed in cells, which bind and cause cross-linking of DNA -- ultimately triggering apoptosis, or automated cell death. Deoxyribonucleic acid ( DNA) is a Nucleic acid that contains the genetic instructions used in the development and functioning of all known

Contents

Pharmacology

Following administration, one of the chloride ligands is slowly displaced by water (an aqua ligand), in a process termed aquation. The aqua ligand in the resulting [PtCl(H2O)(NH3)2]+ is itself easily displaced, allowing cisplatin to coordinate to a basic site in DNA. Deoxyribonucleic acid ( DNA) is a Nucleic acid that contains the genetic instructions used in the development and functioning of all known Subsequently, the platinum cross-links two bases via displacement of the other chloride ligand. [1] Cisplatin crosslinks DNA in several different ways, interfering with cell division by mitosis. Mitosis is the process in which a Eukaryotic cell separates the Chromosomes in its Cell nucleus, into two identical sets in two daughter nuclei The damaged DNA elicits DNA repair mechanisms, which in turn activate apoptosis when repair proves impossible. DNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its Genome.

Most notable among the DNA changes are the 1,2-intrastrand cross-links with purine bases. Purine ( 1) is a heterocyclic Aromatic Organic compound, consisting of a Pyrimidine ring fused to an Imidazole ring These include 1,2-intrastrand d(GpG) adducts which form nearly 90% of the adducts and the less common 1,2-intrastrand d(ApG) adducts. Guanine is one of the five main Nucleobases found in the Nucleic acids DNA and RNA, the others being Adenine, Cytosine, Adenosine is a Nucleoside composed of a Molecule of Adenine attached to a Ribose sugar molecule ( Ribofuranose) moiety via a β-N9- 1,3-intrastrand d(GpXpG) adducts occur but are readily excised by the nucleotide excision repair (NER) . Nucleotides are Organic compounds that consist of three joined structures a nitrogenous base a Sugar, and a Phosphate group Nucleotide excision repair is a DNA repair mechanism DNA constantly requires repair due to damage that can occur to bases from a vast variety of sources including Other adducts include inter-strand crosslinks and nonfunctional adducts that have been postulated to contribute to cisplatin's activity. Interaction with cellular proteins, particularly HMG domain proteins, has also been advanced as a mechanism of interfering with mitosis, although this is probably not its primary method of action. High Mobility Group or HMG is a group of Chromosomal Proteins that help with transcription, replication, Recombination, and DNA

Note that although cisplatin is frequently designated as an alkylating agent, it has no alkyl group and cannot carry out alkylating reactions. It is correctly classified as alkylating-like.

Cisplatin Resistance

Cisplatin combination chemotherapy is the cornerstone of treatment of many cancers. Initial platinum responsiveness is high but the majority of cancer patients will eventually relapse with cisplatin-resistant disease. Many mechanisms of cisplatin resistance have been proposed including changes in cellular uptake and efflux of the drug, increased detoxification of the drug, inhibition of apoptosis and increased DNA repair[2]. DNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its Genome. Oxaliplatin is active in highly cisplatin-resistant cancer cells in the laboratory, however there is little evidence for its activity in the clinical treatment of patients with cisplatin resistant cancer[3]. Oxaliplatin is a Platinum -based Chemotherapy drug in the same family as Cisplatin and Carboplatin. The drug Paclitaxel may be useful in the treatment of cisplatin resistant cancer, the mechanism for this activity is unknown[4]. Paclitaxel is a Mitotic inhibitor used in Cancer Chemotherapy.

Transplatin

Transplatin, the trans stereoisomer of cisplatin, has formula trans-[PtCl2(NH3)2] and does not exhibit a comparably useful pharmacological effect. Trans-2-butenesvg|right|thumb|Trans-2-butene]] In Chemistry, cis-trans isomerism or geometric isomerism or configuration isomerism is a form of Stereoisomers are isomeric molecules that have the same molecular formula and sequence of bonded atoms (constitution but which differ in the three dimensional orientations Its low activity is generally thought to be due to rapid deactivation of the drug before it can arrive at the DNA. It is toxic, and it is desirable to test batches of cis-platin for the absence of the trans isomer. In a procedure by Woollins et al. , which is based on the classic 'Kurnakov test', thiourea reacts with the sample to give derivatives are easily separated and detected by HPLC. Thiourea is an Organic compound of Carbon, Nitrogen, Sulfur and Hydrogen, with the formula C[[Sulfur S]] High-performance liquid chromatography (or High pressure liquid chromatography, HPLC) is a form of Column chromatography used frequently in Biochemistry [5]

Side effects

Cisplatin has a number of side-effects that can limit its use:

History

The compound cis-PtCl2(NH3)2 was first described by M. Peyrone in 1845 (known as Peyrone's salt). [6] The structure was deduced by Alfred Werner in 1893. Alfred Werner ( December 12, 1866 - November 15, 1919) was a Swiss chemist who was a professor at the University [1] In the 1960s, Barnett Rosenberg and van Camp et al at Michigan State University discovered that electrolysis of a platinum electrode produced cisplatin, which inhibited binary fission in Escherichia coli (E. The 1960s decade refers to the years from the beginning of 1960 to the end of 1969 Barnett Rosenberg (born 1926 is an American Chemist best known for the discovery of the anti- Cancer drug Cisplatin. Michigan State University ( MSU) is a co-educational public Research university in East Lansing, Michigan USA. In chemistry and manufacturing electrolysis is a method of separating chemically bonded elements and compounds by passing an Electric current coli) bacteria. The bacteria grow to 300 times their normal length but cell division fails. Rosenberg then conducted a series of experiments to test the effects various platinum coordination complexes on sarcomas artificially implanted in rats. Platinum (ˈplætɪnəm is a Chemical element with the Atomic symbol Pt and an Atomic number of 78 A sarcoma (from the Greek 'sarx' meaning "flesh" is a Cancer of the connective or supportive tissue ( Bone, Cartilage, Fat Rats are various medium sized long-tailed Rodents of the superfamily Muroidea This study found that cis-diamminedichloridoplatinum(II) was the most effective out of this group, which started the medicinal career of cisplatin. [7]

Approved for clinical use by the United States Food and Drug Administration (FDA) in 1978, it revolutionized the treatment of certain cancers. Detailed studies on its molecular mechanism of action, using a variety of spectrocopic methods including X-ray, NMR spectroscopy, and other physico-chemical methods, revealed its ability to form irreversible crosslinks with bases in DNA. In Pharmacology, the term mechanism of action (MOA refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect

Synthesis

The synthesis of cisplatin is a classic in inorganic chemistry. Inorganic chemistry is the branch of Chemistry concerned with the properties and behavior of Inorganic compounds This field covers all Chemical compounds Starting from potassium tetrachloroplatinate(II), K2PtCl4, the first NH3 ligand is added to any of the four equivalent positions, but the second NH3 could be added cis or trans to the bound amine ligand. Potassium tetrachloroplatinate(II is the Chemical compound with the formula K2PtCl4 In Chemistry, a ligand is either an Atom, Ion, or Molecule (see also Functional group) that bonds to a central metal generally Because Cl− has a larger trans effect than NH3, the second amine preferentially substitutes trans to a chloride ligand, and therefore cis to the original amine. In Inorganic chemistry, the trans effect is the labilization of Ligands Trans to certain other ligands which can thus be regarded as trans directing ligands The trans effect of the halides follows the order I->Br->Cl-, therefore the synthesis is conducted using PtI42− to ensure high yield and purity of the cis isomer, followed by conversion of the PtI2(NH3)2 into PtCl2(NH3)2, as first described by Dhara. [8][9]

Synthesis of cisplatin

References

  1. ^ a b Stephen Trzaska (20 Jun 05). "Cisplatin". C&EN News 83 (25). Chemical & Engineering News is a weekly chemistry news magazine published by the American Chemical Society.  
  2. ^ Stordal, B. and Davey, M. (2007). Understanding cisplatin resistance using cellular models. IUBMB Life. 59(11) 696-699. [1]
  3. ^ Stordal, B. , Pavlakis, N. and Davey, R. (2007). Oxaliplatin for the treatment of cisplatin-resistant cancer: A systematic review. Cancer Treatment Reviews. 33(4)347-357 [2]
  4. ^ Stordal, B. , Pavlakis, N. and Davey, R. (2007). A systematic review of platinum and taxane resitance from bench to clinic: An inverse relationship. Cancer Treatment Reviews. 33:688-703. [3]
  5. ^ J. D. Woollins, A. Woollins and B. Rosenberg (1983). "The detection of trace amounts of trans-Pt(NH3)2Cl2 in the presence of cis-Pt(NH3)2Cl2. A high performance liquid chromatographic application of kurnakow's test". Polyhedron 2 (3): 175-178. What is a polyhedron? We can at least say that a polyhedron is built up from different kinds of element or entity each associated with a different number of dimensions doi:10.1016/S0277-5387(00)83954-6. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document.  
  6. ^ Peyrone M. Ann Chemie Pharm 1845;51:129.
  7. ^ Rosenberg, B. ; Van Camp, L. ; Krigas, T. (1965). "Inhibition of cell division in Escherichia coli by electrolysis products from a platinum electrode". Nature 205 (4972): 698-699. Nature is a prominent Scientific journal, first published on 4 November 1869 doi:10.1038/205698a0. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document.  
  8. ^ Dhara, S. C. Indian Journal of Chemistry 1970, volume 8, pp. 193–134.
  9. ^ Rebecca A. Alderden, Matthew D. Hall, and Trevor W. Hambley (2006). "The Discovery and Development of Cisplatin" (abstract). J. Chem. Ed. 83: 728-724. The Journal of Chemical Education ( JCE) is a monthly subscription-only periodical available in both print and electronic versions  

External links

Dictionary

cisplatin

-noun

  1. (oncology, pharmacology) A simple organic compound of platinum, cis-diamminedichloroplatinum(II), that is used as a chemotherapy agent against several types of cancer.
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