How does cisplatin identify cancer cells



Characteristics
Name (INN) Cisplatin
Other names

DDP

Impact group

Cytostatic

Trade names

Cisplatin® (D)

classification
ATC code XA01
CAS number 15663-27-1
Prescription Required: Yes

Cisplatin (DDP) is a very common cytostatic agent (agent to inhibit cell growth or cell division). The chemical structure contains a complex bonded platinum atom. The effect against cancer cells is based on a cross-linking of the DNA molecules (genetic material), which thereby become inoperable. The cell metabolism is hindered and the cell dies. Like other cytostatics, cisplatin not only acts in this way on fast-growing tumor cells, but to a certain extent also on healthy body cells.

chemistry

Cisplatin is a planar complex that has two cis chloro ligands and two ammine ligands attached to the central platinum atom. (For a more detailed explanation of the nomenclature of complex compounds, see complex chemistry) The compound must first be activated, whereby intracellularly (low chloride concentration!) The chlorine ligands are replaced by water (aqua ligands).

pharmacology

Mechanism of action

Cisplatin has a similar effect to bifunctional alkylating agents by cross-linking DNA strands. Due to the high nucleophilicity of the aqua-cisplatin complex, cisplatin reacts preferentially with the N-7 of guanine and adenine. This creates links within a DNA strand (intra-strand cross-linking) and between adjacent 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 operating principles of cisplatin lead to the activation of the programmed cell death apoptosis in rapidly dividing cells.

Resistance Mechanism

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. CTR1 - a transport protein that is normally responsible for the uptake of copper into the cell. Increased DNA repair is also said to be involved. Note the cross-resistance with carboplatin.

Pharmacokinetics

Cisplatin would be hydrolyzed by the stomach 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 (talpha = 20-30 min, tbeta = 40-70 min, tgamma = 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, 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 in the head and neck area. 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 lead to nausea, vomiting and diarrhea. Using modern antiemetics like 5-HT3-Antagonists (e.g. ondansetron) and aprepitant, this very unpleasant side effect can now be influenced quite well.
  • 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.
  • Hearing damage in the higher frequencies (especially in children).
  • After repeated administration possibly peripheral neuropathy with paresthesia, cramps and loss of motor functions.
  • Bone marrow suppression.
  • in rare cases anaphylactoid reactions (anaphylaxis).

literature

  • Wieland Voigt, Andrea Dietrich, Hans-Joachim Schmoll: Cisplatin and its analogues. Pharmacy in our time 35 (2), pp. 134 - 143 (2006), ISSN 0048-3664
  • Markus Galanski, Bernhard K. Keppler: Metal anti-tumor compounds. Pharmacy in our time 35 (2), pp. 118-122 (2006), ISSN 0048-3664
  • Bernhard Lippert (Ed.): Cisplatin, Chemistry and Biochemistry of a Leading Anticancer Drug. Wiley-VCH (1999), ISBN 3-906390-20-9

Categories: Drugs | Platinum compound