General Description
An anticancer drug. Orange-yellow to deep yellow solid or powder.
Reactivity Profile
PLATINOL(15663-27-1) is incompatible with oxidizing agents. PLATINOL(15663-27-1) is also incompatible with aluminum. PLATINOL(15663-27-1) may react with sodium bisulfite and other antioxidants.
Air & Water Reactions
Insoluble in water.
Potential Exposure
A potential danger to those involved in the manufacture, formulation and administration of this anticancer chemotherapy agent. Contact with water causes decomposition.
Fire Hazard
Flash point data for this chemical are not available; however, PLATINOL is probably combustible.
First aid
If this chemical gets into the eyes, remove any contact lenses at once and irrigate immediately for at least 15 minutes, occasionally lifting upper and lower lids. Seek medical attention immediately. If this chemical contacts the skin, remove contaminated clothing and wash immediately with soap and water. Seek Medical attention immediately. If this chemical has been inhaled, remove from exposure, begin rescue breathing (using universal precautions, including resuscitation mask) if breathing has stopped and CPR if heart action has stopped. Transfer promptly to a medical facility. When this chemical has been swallowed, get medical attention. Give large quantities of water and induce vomiting. Do not make an unconscious person vomit
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
Incompatibilities
Aluminum reacts with cisplatin and decreases the drug’s effectiveness. Do not use any aluminum equipment to prepare or administer cisplatin.
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.
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
Originator
Blastolem,Lemery,Mexico
Uses
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.
Definition
ChEBI: 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
Pharmaceutical Applications
CDDP, also referred to as cisplatinum or cisplatin, is a yellow powder and has found widespread use a
chemotherapeutic agent.
Biological Activity
Potent anticancer agent that blocks DNA synthesis. Induces apoptosis via p53-dependent and -independent mechanisms. Inhibits X-linked inhibitor of apoptosis protein (XIAP) expression and activates caspase-3. In certain glioma cell lines, sensitizes cells to TNF- α -induced apoptosis.
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.
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.
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) .
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.
Carcinogenicity
Cisplatin is reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in experimental animals.
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.
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.
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.M4101032002) Siddik et al. (2003), Cisplatin: mode of cytotoxic action and molecular basis of resistance; Oncogene, 22 7265 DOI:
10.1038/sj.onc.12069333) 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/s0028000500304) 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.2004.04.0355) 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:
10.4103/0253-7613.1571326) 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)
