Cisplatin

Structural formula
General
Non-proprietary name	Cisplatin
other names	(SP-4-2) -diammine dichloridoplatinum (II) ( IUPAC )
Molecular formula	[Pt (NH 3 ) 2 Cl 2 ]
Brief description	Yellow, odorless powder
External identifiers / databases
CAS number 15663-27-1 EC number 239-733-8 ECHA InfoCard 100.036.106 PubChem 5702198 DrugBank DB00515 Wikidata Q412415
Drug information
ATC code	L01 XA01
Drug class	Cytostatic
properties
Molar mass	300.05 g mol −1
Physical state	firmly
density	3.7 g cm −3 (20 ° C)
Melting point	270 ° C (decomposition)
solubility	poor in water (2.5 g l −1 at 20 ° C)
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS labeling of hazardous substances danger H and P phrases H: 300-312-315-318-332-335-350 P: 330-302 + 352-304 + 340-332 + 313-305 + 351 + 338-310-280
MAK	0.002 mg m −3
Toxicological data	25.8 mg kg −1 ( LD 50 ,  rat ,  oral )
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Cisplatin ( cis -diamminedichloridoplatin; DDP) is a medicinal substance ( cytostatic to inhibit cell growth or cell division) and contains a complex-bound platinum atom . The effect is based on an inhibition of DNA replication through cross-linking of two neighboring guanine bases of a DNA strand . This disrupts the structure of the DNA and makes it inoperable. The cell metabolism comes to a standstill and the cell initiates apoptosis . Like other cytostatic agents, cisplatin does not only act on fast-growing tumor cells , but to a certain extent also on healthy body cells.

history

Cisplatin was first synthesized by Michele Peyrone in 1844 , then known as Peyrones Chloride. It played a role in the development of complex chemistry by Alfred Werner . The discovery of the cytostatic effect of platinum complexes occurred purely by chance in the 1960s. Barnett Rosenberg wanted to study the effect of alternating current on the growth of Escherichia coli . He used platinum electrodes for this and found that cell growth was inhibited. After some scientific detective work, the cause was not found to be the alternating current, but the complex compound cis -diammine tetrachloridoplatinum (IV), [Pt (NH ₃ ) ₂ Cl ₄ ], which had formed from the supposedly inert platinum electrodes. Subsequent tests with the longest known complex compound of platinum, cis -diammine dichloridoplatinum (II), [Pt (NH ₃ ) ₂ Cl ₂ ], showed the same effect with regard to growth inhibition. In contrast, studies with the corresponding trans compound showed no effect. Diamminedichloridoplatinum (II) had been known as Peyrones' salt or Reiset's second chloride since 1844 , although later studies showed that both compounds were cis and trans isomers . The existence of the two isomers led Alfred Werner to conclude in 1894 that both complexes have a planar structure.

In cancer therapy, cisplatin was first used in 1974 as part of a study at Indiana University Hospital for the treatment of testicular cancer , and in the following years it led to significant successes in a large number of patients without a relapse . Because antiemetics were not so widespread at the time , the therapy was associated with extremely strong nausea for the patients.

chemistry

Cisplatin is a planar complex is that on the central platinum atom two cis -ständige chloride ligand and two ammine ligands bound (for a more detailed explanation of the nomenclature of complex compounds see complex chemistry ). The compound must first be activated by replacing the chloride ligands with water intracellularly due to the lower chloride concentration; various aqua and hydroxido complexes are formed through hydrolysis , some of which oligomerize via hydroxido bridges . Cisplatin is produced by the reaction of dipotassium tetrachloridoplatinate (II) (K ₂ [PtCl ₄ ]) with ammonia using the trans effect .

pharmacology

Schematic mechanism of formation of the cisplatin-DNA adduct. Cross-links are established between the platinum and two guanines of the DNA. The effect of cisplatin has been studied intensively. Cisplatin has been approved as an anti-cancer agent since 1973.

Mechanism of action

Cisplatin has a similar effect to bifunctional alkylating agents by cross-linking DNA strands. Due to the high electrophilicity of the aqua-cisplatin complex, cisplatin reacts preferentially with the N ₇ atom of guanine and adenine . This creates links within a DNA strand (intra-strand cross-linking) and between neighboring DNA strands (inter-strand cross-linking). Another important principle of action of cisplatin is the triggering of point mutations . In addition to these effects, cisplatin also inhibits DNA repair and inhibits telomerase activity . These principles of action of cisplatin lead to the activation of programmed cell death (apoptosis) in rapidly dividing cells.

Mechanism of resistance

Intracellular concentrations of glutathione and the metalloproteins carrying numerous SH groups, which bind and inactivate the platinum compounds, are said to be important for the development of resistance . Transport proteins also play an important role in the development of resistance, e.g. B. CTR1 - a transport protein that is normally responsible for the uptake of copper into the cell. Increased DNA repair should also be involved. Note the cross-resistance with carboplatin .

Pharmacokinetics

Cisplatin would be hydrolyzed by gastric acid if it was taken orally, so it is administered intravenously . 90% of it is bound to serum proteins (e.g. albumin ) and is subject to three-phase elimination kinetics (t _alpha  = 20-30 min, t _beta  = 40-70 min, t _gamma  = 24 h). In the tertiary phase, the plasma protein-bound cisplatin is eliminated. The distribution of cisplatin shows particularly high concentrations in the kidneys , liver , gonads , spleen , prostate , urinary bladder , pancreas , muscles and adrenal glands . The uptake in the brain and in the cerebrospinal fluid is low.

indication

The main areas of application for cisplatin are testicular , ovarian , bronchial , bladder and cervical carcinoma and squamous cell carcinoma of the head and neck as well as chorionic carcinoma . Cisplatin is administered as an infusion and is used almost exclusively in combination with other chemotherapeutic agents (combination chemotherapy ).

unwanted effects

• Cisplatin is one of the cytostatics that most commonly cause nausea, vomiting and diarrhea. However , these very unpleasant side effects can now be influenced quite well using modern antiemetics such as 5-HT ₃ antagonists (e.g. ondansetron ) and aprepitant .
• Dose-limiting kidney damage (about 2nd week after the start of therapy). Increased diuresis and adequate fluid intake before, during and after use can reduce nephrotoxicity. Diuretics , especially loop diuretics , increase nephrotoxicity and are therefore contraindicated.
• Hearing damage in the higher frequencies (especially in children).
• After repeated administration possibly peripheral neuropathy with paresthesias , cramps and loss of motor functions.
• Myelosuppression
• In rare cases, anaphylactoid reactions ( anaphylaxis ).

The negative effects of cisplatin on the healthy cells of some organs, such as the kidneys, can be partially suppressed by the approved cytoprotector amifostine .

Trade names

Monopreparations
Cis-GRY (D), Platiblastin (CH), Platinol (CH), numerous generics (D, A, CH).

literature

• Markus Galanski, Bernhard K. Keppler: Tumor-inhibiting metal compounds . In: Pharmazie in our time 35 (2), pp. 118-122 (2006), doi: 10.1002 / pauz.200500160
• Ingo Ott, Ronald Gust: Medicinal chemistry of platinum complexes: special features of inorganic cytostatics . In: Pharmazie in our time 35 (2), 2006, pp. 124-133, doi: 10.1002 / pauz.200500161
• Wieland Voigt, Andrea Dietrich, Hans-Joachim Schmoll: Cisplatin and its analogues . In: Pharmazie in our time 35 (2), 2006, pp. 134-143, doi: 10.1002 / pauz.200500162
• Bernhard Lippert (Ed.): Cisplatin, Chemistry and Biochemistry of a Leading Anticancer Drug . Wiley-VCH, 1999, ISBN 3-906390-20-9
• Bernhard Lippert, Wolfgang Beck: Platinum complexes in cancer therapy . In: Chemistry in our time , 17th year 1983, No. 6, pp. 190-199, doi: 10.1002 / ciuz.19830170604

Individual evidence

1. ↑ ^{a b c d e f g h} Entry on cisplatin in the GESTIS substance database of the IFA , accessed on January 14, 2020(JavaScript required) .
2. ^ Siddhartha Mukherjee : The king of all diseases: Cancer - a biography . DuMont Buchverlag, Cologne 2012, ISBN 978-3-8321-9644-8 .
3. ↑ B. Lippert (Ed.): CISPLATIN - Chemistry and Biochemistry of a Leading Anticancer Drug. 1999, WILEY-VCH, pp. 84-85.
4. ↑ FDA Oncology Tools Approval Summary for cisplatin for Metastatic ovarian tumors . ( Memento of February 8, 2008 in the Internet Archive ) fda.gov; Retrieved October 21, 2010
5. ↑ KK Filipski, RH Mathijssen u. a .: Contribution of organic cation transporter 2 (OCT2) to cisplatin-induced nephrotoxicity. In: Clinical Pharmacology and Therapeutics . Volume 86, Number 4, October 2009, pp. 396-402, doi: 10.1038 / clpt.2009.139 . PMID 19625999 . PMC 2746866 (free full text).
6. ↑ S. Waissbluth, SJ DANIEL cisplatin-induced ototoxicity: Transporters playing a role in cisplatin toxicity. In: Hearing research. Volume 299, May 2013, pp. 37-45, doi: 10.1016 / j.heares.2013.02.002 . PMID 23467171 .
7. ↑ JM Yuhas, JM Spellman, F. Culo: The role of WR-2721 in radiotherapy and / or chemotherapy. In: Cancer Clinical Trials Volume 3, Number 3, 1980, pp. 211-216, PMID 6254681 .
8. ↑ Amifostine for cytoprotection against side effects of combination therapy with cyclophosphamide and cisplatin in patients with ovarian cancer. ( Memento from January 23, 2011 in the Internet Archive ) In: Der Arzneimittelbrief , Volume 31, 1997, 6b.
9. ^ LG Marcu: The role of amifostine in the treatment of head and neck cancer with cisplatin-radiotherapy. In: European Journal of Cancer Care Volume 18, Number 2, March 2009, pp. 116-123, doi: 10.1111 / j.1365-2354.2008.01032.x . PMID 19267726 . (Review).
10. ↑ M. Treskes, U. Holwerda, I. Klein, HM Pinedo, WJ van der Vijgh: The chemical reactivity of the modulating agent WR2721 (ethiofos) and its main metabolites with the antitumor agents cisplatin and carboplatin. In: Biochemical pharmacology Volume 42, Number 11, November 1991, pp. 2125-2130, PMID 1659819 .
11. ↑ Red List online, as of September 2009
12. ↑ AM comp. d. Switzerland, as of September 2009
13. ↑ AGES-PharmMed, as of September 2009

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