Cisplatin Ebewe Mechanism of Action

Pharmacology: Pharmacodynamics: Antineoplastic agents, other antineoplastic agents, platinum compounds.
Cisplatin is an anorganic substance containing a heavy metal [cis-diamminedichloroplatinum(II)]. This substance inhibits the DNA synthesis by realising transverse connections within and between the DNA strings.
The protein and RNA synthesis is inhibited to a lesser extent.
Although the primary activity of cisplatin seems to be the inhibition of DNA synthesis, the antineoplastic process includes other activities, such as enlargement of the tumour immunogenicity. Cisplatin's oncolytic functions can be compared to the functions of alkylating substances. Cisplatin also offers immunosuppressive, radiosensitising and antibacterial features.
Cisplatin does not seem to be cell cycle specific.
The cytotoxic activities of cisplatin are caused by binding all DNA bases, with a preference for the N-7 position of guanine and adenosine.
Pharmacokinetics: After intravenous administration, cisplatin is rapidly distributed among all tissues. Following cisplatin doses of 20 to 120 mg/m², the concentrations of platinum are highest in liver, prostate and kidney, somewhat lower in bladder, muscles, testicle, pancreas and spleen and lowest in bowel, adrenal, heart, lung, cerebrum and cerebellum. Over 90% of the total plasma cisplatin is bounded with protein after two hours following the administration. This process may be irreversible. The protein-bounded part is not antineoplastic active. Cisplatin is non-linearly pharmacokinetic.
Cisplatin is converted by a non-enzymatic process into one or more metabolites. Elimination from the plasma is realised in two phases after intravenous bolus injection of 50-100 mg/m², of cisplatin.
The following half-life period have been registered for humans: t½ (distribution): 10-60 minutes; t½ (terminal): approximately 2-5 days.
The considerable protein binding of the total platinum contents results in an extended or incomplete excretion phase with cumulative urine secretion ranging from 27 to 45% of the administered dose in a period from 84 to 120 hours. An extended infusion results in the urine secretion of a larger part of the dose. The faecal secretion is minimal, and small amounts of platinum can be traced in the gallbladder and the large intestine. Dysfunctional kidneys increase the plasma half-life period, which may also increase theoretically in the presence of ascites caused by the highly protein binding activities of cisplatin.
Toxicology: Preclinical safety data: Chronic toxicity: Chronic toxicity models indicate kidney damage, bone marrow depression, gastrointestinal disorders and ototoxicity.
Mutagenicity and carcinogenicity: Cisplatin is mutagenic in numerous in vitro and in vivo tests (bacterial test systems and chromosome defects in animal cells and tissue cultures). Long-term studies of cisplatin on mice and rats evidenced the carcinogenic effects.
Reproductive toxicity: Fertility: Gonadal suppression resulting in amenorrhoea or azoospermia may be irreversible and cause definitive infertility.
Studies in rats showed that exposure during pregnancy produces tumours in the adult offspring.
Pregnancy and lactation: Cisplatin is embryotoxic and teratogenic for mice and rats, and defects have been reported for both species. Cisplatin was found in the milk.