Cisplatin

Absorption

Following cisplatin doses of 20 to 120 mg/m^2, the concentrations of platinum are highest in liver, prostate, and kidney; somewhat lower in bladder, muscle, testicle, pancreas, and spleen; and lowest in bowel, adrenal, heart, lung, cerebrum, and cerebellum. Platinum is present in tissues for as long as 180 days after the last administration.

Description

Cisplatin is a platinum-containing compound that acts as a DNA-crosslinking agent and interferes with replication and transcription, culminating in apoptosis. It forms intra- and interstrand crosslinks with DNA with intrastrand guanine-to-guanine or guanine-to-alanine links accounting for the majority of DNA binding. Cisplatin halts the cell cycle at the G₂/M phase in vitro and is active against murine tumors transplanted into mice and in mouse xenograft models, including a reduction in tumor growth in a model of squamous cell carcinoma of the head and neck when administered at doses ranging from 7.5 to 12.5 mg/kg. Cisplatin also inhibits the RecA recombinase of M. tuberculosis (IC₅₀ = 2 μM), blocking protein splicing and cell growth. Formulations containing cisplatin have been used, alone and in combination therapy, in the treatment of a variety of cancers.

Description

Cisplastin is an non-organic platinum-containing drug with alkylating properties. It causes cross-linking of DNA and RNA chains. In particular, it has been shown, that cisplastin, like other alkylating agents, bind primarily at N7 of two neighboring deoxyguanylates to DNA, which inhibits its replication. It is only used intravenously. It is highly reactive with carcinomas of the testicles, ovaries, heat, neck, spleen, lungs, and so on.

Chemical properties

Cisplatin is a white powder or yellow crystalline solid with the melting point 268-272°C (decomposition). It is slightly soluble in water and easily soluble in dimethylformamide. In aqueous solution, it can be gradually transformed into trans-and hydrolysis.

Originator

Blastolem,Lemery,Mexico

The Uses of Cisplatin

Cisplatin is a cytostatic agent and it is used to treat various cancer types, including cancer of ovary, testis, lung, head, neck, bladder, neuroblastoma, and nephroblastoma, and Hodgkin’s disease and non-Hodgkin lymphoma.

The Uses of Cisplatin

cisplatin is a platinum complex, cis-[PtCl2(NH3)2], used in cancer treatmentto inhibit the growth oftumours. It acts by binding betweenstrands of DNA.

Background

Cisplatin, cisplatinum or cis-diamminedichloroplatinum(II) (CDDP) is a platinum-based chemotherapy drug used to treat various types of cancers, including sarcomas, some carcinomas (e.g. small cell lung cancer, and ovarian cancer), lymphomas and germ cell tumors. It was the first member of its class, which now also includes carboplatin and oxaliplatin.

Indications

For the treatment of metastatic testicular tumors, metastatic ovarian tumors and advanced bladder cancer.

Definition

ChEBI: Cisplatin is a diamminedichloroplatinum compound in which the two ammine ligands and two chloro ligands are oriented in a cis planar configuration around the central platinum ion. An anticancer drug that interacts with, and forms cross-links between, D A and proteins, it is used as a neoplasm inhibitor to treat solid tumours, primarily of the testis and ovary.

Indications

Cisplatin (Platinol) is an inorganic coordination complex with a broad range of antitumor activity. It is especially useful in the treatment of testicular and ovarian cancer. It binds to DNA at nucleophilic sites, such as the N7 and O6 of guanine, producing alterations in DNA structure and inhibition of DNA synthesis. Adjacent guanine residues on the same DNA strand are preferentially cross-linked. This platinating activity is analogous to the mode of action of alkylating agents. Cisplatin also binds extensively to proteins. It does not appear to be phase specific in the cell cycle.

Production Methods

Cisplatin is obtained by the method described by Kauffman and Cowan, in which potassium(II) tetrachloroplatinate is treated with buffered aqueous ammonia solution. Pure cisplatin is obtained by recrystallization from dilute hydrochloric acid.

Manufacturing Process

The synthesis proceeds dy reduction of potassium hexachlorplatinate with hydrazine to give potassium tetrachloroplatinate. This is converted to potassium tetraiodoplatinate by treatment with potassium iodide and then reacted with 6 M ammonium hydroxide to give crystals of cisplatin

Therapeutic Function

Antitumor

General Description

An anticancer drug. Orange-yellow to deep yellow solid or powder.

General Description

administrationin the treatment of a wide variety of cancers includingnon-Hodgkin’s lymphoma, bladder cancer, ovarian cancer,testicular cancer, and cancers of the head and neck. A liposomalform is also available as well as an injectable collagenmatrix gel containing cisplatin. Compared with other platins,cisplatin is the most reactive and therefore the most effectivein platinating DNA. After IV administration, the agent iswidely distributed, highly protein bound (90%), and concentratesin the liver and kidney. After infusion, covalent attachmentto plasma proteins occurs such that after 4 hours, 90%of drug is protein bound. The elimination of platinum fromthe blood is a slow process with a terminal elimination halflifeof 5 to 10 days. Metabolism involves aquation, which occursto a greater extent once distribution out of the plasmahas occurred. Additional metabolites have been seen resultingfrom reaction with glutathione and cysteine. The greaterreactivity of cisplatin gives rise to significant toxicitiescompared with other platins. These include dose-limitingnephrotoxicity, which normally presents as elevated bloodurea nitrogen (BUN) and creatinine. This effect is cumulativeupon repeated dosing and may progress further to necrosis,altered epithelial cells, cast formation, and thickening ofthe tubular basement membranes but is generally reversibleupon discontinuation of drug treatment. Sodium thiosulfatemay be given to reduce the nephrotoxicity. Neurotoxicitymay also be dose limiting, normally presenting initially asnumbness but may progress to seizure. Other adverse effectsinclude myelosuppression, nausea, vomiting, alopecia,ototoxicity, ocular toxicity, azoospermia, impotence, myocardialinfarction, thrombotic events, and inappropriatesecretion of antidiuretic hormone.

Air & Water Reactions

Insoluble in water.

Reactivity Profile

Cisplatin is incompatible with oxidizing agents. Cisplatin is also incompatible with aluminum. Cisplatin may react with sodium bisulfite and other antioxidants.

Fire Hazard

Flash point data for Cisplatin are not available; however, Cisplatin is probably combustible.

Pharmaceutical Applications

CDDP, also referred to as cisplatinum or cisplatin, is a yellow powder and has found widespread use a chemotherapeutic agent.

Biological Activity

Cisplatin is a platinum-containing compound that acts as a DNA-crosslinking agent and interferes with replication and transcription, culminating in apoptosis. It forms intra- and interstrand crosslinks with DNA with intrastrand guanine-to-guanine or guanine-to-alanine links accounting for the majority of DNA binding. Cisplatin halts the cell cycle at the G2/M phase in vitro and is active against murine tumors transplanted into mice and in mouse xenograft models, including a reduction in tumor growth in a model of squamous cell carcinoma of the head and neck when administered at doses ranging from 7.5 to 12.5 mg/kg. Cisplatin also inhibits the RecA recombinase of M. tuberculosis (IC50 = 2 μM), blocking protein splicing and cell growth. Formulations containing cisplatin have been used, alone and in combination therapy, in the treatment of a variety of cancers.

Biochem/physiol Actions

Potent platinum-based antineoplastic agent. Forms cytotoxic adducts with the DNA dinucleotide d(pGpG), inducing intrastrand cross-links.

Mechanism of action

Cisplatin shows biphasic plasma decay with a distribution phase half-life of 25 to 49 minutes and an elimination half-life of 2 to 4 days. More than 90% of the drug is bound to plasma proteins, and binding may approach 100% during prolonged infusion. Cisplatin does not cross the blood-brain barrier. Excretion is predominantly renal and is incomplete.

Pharmacokinetics

Cisplatin is an antineoplastic in the class of alkylating agents and is used to treat various forms of cancer. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumor growth by cross-linking guanine bases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn inhibits their correct utilization by base pairing and causes a miscoding of DNA. Alkylating agents are cell cycle-nonspecific. Alkylating agents work by three different mechanisms all of which achieve the same end result - disruption of DNA function and cell death.

Clinical Use

Cisplatin, combined with bleomycin and vinblastine or etoposide, produces cures in most patients with metastatic testicular cancer or germ cell cancer of the ovary. Cisplatin also shows some activity against carcinomas of the head and neck, bladder, cervix, prostate, and lung.

Side Effects

Renal toxicity is the major potential toxicity of cisplatin. Severe nausea and vomiting that often accompany cisplatin administration may necessitate hospitalization. Cisplatin has mild bone marrow toxicity, yielding both leukopenia and thrombocytopenia. Anemia is common and may require transfusions of red blood cells. Anaphylactic allergic reactions have been described. Hearing loss in the high frequencies (4000 Hz) may occur in 10 to 30% of patients. Other reported toxicities include peripheral neuropathies with paresthesias, leg weakness, and tremors. Excessive urinary excretion of magnesium also may occur.

Safety Profile

Confirmed carcinogen with experimental carcinogenic and tumorigenic data. Poison by ingestion, intramuscular, submtaneous, intravenous, and intraperitoneal routes. Human systemic effects: change in audttory acuity, change in kidney tubules, changes in bone marrow, corrosive to skin, depressed renal function tests, hallucinations, nausea or vomiting. Experimental teratogenic and reproductive effects. Human mutation data reported. When heated to decomposition it emits very toxic fumes of Cland NOx. See also PLATINUM COMPOUNDS.

Synthesis

Cisplatin, cis-diaminodichloroplatinum (30.2.5.1), is made by reducing potassium hexachloroplatinate by hydrazine to potassium tetrachloroplatinate, which reacts with ammonia to give cisplatin (30.2.5.1) .

Potential Exposure

A potential danger to those involved in the manufacture, formulation and administration of this anticancer chemotherapy agent. Contact with water causes decomposition.

Veterinary Drugs and Treatments

In veterinary medicine, the systemic use of cisplatin is presently limited to use in dogs. The drug has been, or may be, useful in a variety of neoplastic diseases including squamous cell carcinomas, transitional cell carcinomas, ovarian carcinomas, mediastinal carcinomas, osteosarcomas, pleural adenocarcinomas, nasal carcinomas, and thyroid adenocarcinomas.
Cisplatin may be useful for the palliative control of neoplastic pulmonary effusions after intracavitary administration.
In horses, cisplatin has been used for intralesional injection for skin tumors.

Drug interactions

Potentially hazardous interactions with other drugs
Aldesleukin: avoid concomitant use.
Antibacterials: increased risk of nephrotoxicity and possibly ototoxicity with aminoglycosides, capreomycin, polymyxins or vancomycin.
Antipsychotics: avoid with clozapine, increased risk of agranulocytosis.
Cytotoxics: increased risk of ototoxicity with ifosfamide; increased pulmonary toxicity with bleomycin and methotrexate.

First aid

If this chemical gets into the eyes, remove anycontact lenses at once and irrigate immediately for at least15 min, occasionally lifting upper and lower lids. Seek medical attention immediately. If this chemical contacts theskin, remove contaminated clothing and wash immediatelywith soap and water. Seek medical attention immediately. Ifthis chemical has been inhaled, remove from exposure,begin rescue breathing (using universal precautions, including resuscitation mask) if breathing has stopped and CPR ifheart action has stopped. Transfer promptly to a medicalfacility. When this chemical has been swallowed, get medical attention. Give large quantities of water and inducevomiting. Do not make an unconscious person vomit.

Carcinogenicity

Cisplatin is reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in experimental animals.

Metabolism

Not Available

Metabolism

It is rapidly hydrated, resulting in a short plasma half-life of less than 30 minutes. It is eliminated predominantly via the kidney, but approximately 10% of a given dose undergoes biliary excretion. It is highly nephrotoxic and can cause significant damage to the renal tubules, especially in patients with preexisting kidney disease or one kidney or who are concurrently receiving other nephrotoxic drugs (e.g., cyclophosphamide or ifosfamide). Dosages should be reduced in any of the above situations. Clearance decreases with chronic therapy, and toxicities can manifest at a late date. To proactively protect patients against kidney damage, patients should be hydrated with chloride-containing solutions. Saline or mannitol diuretics can be administered to promote continuous excretion of the drug and its hydrated analogues. Sodium thiosulfate, which accumulates in the renal tubules, also has been used to neutralize active drug in the kidneys in an effort to avoid nephrotoxicity.

storage

Room temperature

Shipping

UN2928 Toxic solids, corrosive, organic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials, 8-Corrosive material, Technical Name Required. UN3290 Toxic solid, corrosive, inorganic, n.o.s., Hazard class: 6.1; Labels: 6.1-Poisonous materials, 8-Corrosive material. UN3288 Toxic solids, inorganic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials, Technical Name Required. UN3249 Medicine, solid, toxic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials

Purification Methods

Recrystallise it from dimethylformamide and check the purity by IR and UV-VIS spectroscopy. [Raudaschl et al. Inorg Chim Acta 78 143 1983.] HIGHLY TOXIC, SUSPECTED CARCINOGEN.

Incompatibilities

Aluminum reacts with cisplatin and decreases the drug’s effectiveness. Do not use any aluminum equipment to prepare or administer cisplatin.

Waste Disposal

Disposal of unused product must be undertaken by qualified personnel who are knowledgeable in all applicable regulations and follow all pertinent safety precautions including the use of appropriate protective equipment. For proper handling and disposal, always comply with federal, state, and local regulations

References

1) Van Waardenburg et al. (2004), Platinated DNA adducts enhance poisoning of DNA topoisomerase I by camptothecin; J. Biol. Chem,, 279 54502 DOI:10.1074/JBC.M410103200
2) Siddik et al. (2003), Cisplatin: mode of cytotoxic action and molecular basis of resistance; Oncogene, 22 7265 DOI:10.1038/sj.onc.1206933
3) Seki et al. (2000), Cisplatin (CDDP) specifically induces apoptosis via sequential activation of caspase-8, -3 and -6 in osteosarcoma; Cancer Chemother. Pharmacol., 45 199 DOI:10.1007/s002800050030
4) Nomura et al. (2004), Cisplatin inhibits the expression of X-linked inhibitor of apoptosis protein in human LNCaP cells; Urol. Oncol., 22 453 DOI:10.1016/J.UROLONC.2004.04.035
5) Raghavan et al. (2015), Dimethylsulfoxide inactivates the anticancer effect of cisplatin against myelogenous leukemia cell lines in in vitro assays.; Indian J. Phamracol., 47 322 DOI:10.4103/0253-7613.157132
6) Synthesis of Essential Drugs (2006, Elsevier) - libgen.lc
7) Sittig's Pharmaceutical Manufacturing Encyclopedia
8) Patty's Toxicology 6-Volume Set-Wiley (2012)
9) Modern pharmacology with clinical applications (2004, LWW)