History of discovery
Cisplatin is currently one of the most commonly used drugs used in combination chemotherapy with its chemical full name being cis-dichlorodiamineplatinum. It belongs to inorganic metal complexes. After the dissociation of the chlorine atom, it can be cross-linked with the DNA of the cancer cell DNA, thereby destroying the DNA function. It can form intra-strand or inter-strand crosslink with the DNA and may also form a cross-link with DNA and protein, and can inhibit cell mitosis, belonging to cell cycle non-specific drugs. In addition to its anti-cancer effect, it is still capable of inhibiting lymphocyte transformation and having immunosuppression effect and thus can be used as the metal complex-class anti-cancer drugs.
In 1844, it had been first successfully developed by the French chemist Mario Rampini and has been ever called Rampini's salt. It appears as an orange crystal. It has a small solubility (being 0.252 g/ 100 g of water at 25 ℃) and can be produced through the reaction between tetrachloro platinum (II) solution of potassium and ammonia.
In 1891, the modern founder of coordination chemistry, Werner, starting from the study of this class of compounds, had successfully established a complex theory, and clarified the cis structure of the Rampini's salt.
It was not until 1965 that the anticancer activity of cisplatin was found by Rosenberg and his colleagues from University of Michigan USA. When studying the effect of the electric filed on the growth of E. coli, they found that when putting into the metallic platinum to the medium containing ammonium chloride and then sending through 2 ampere for two hours, the reproduction of E. coli was inhibited.
Further studies had showed that this is the effect of the cisplatin which is the product produced through the chemical reaction between the ammonia chloride and the platinum ion produced by electrolytic oxidation in the electrode. Rosenberg thought that given that cisplatin can prevent cell division, it should also have anticancer activity. Through the anti-cancer test, it has been proven that there is a good anti-cancer effect of cisplatin, drawing broad interest in metal complexes pharmacology. People had organized international cooperation research on chemistry, biology and medical field, finally enabling the successful applications of cisplatin in the treatment of cancer.
In December 1978, the US Food and Drug Administration had approved cisplatin for clinical application and make it as a commodity to supply the market. It has properties such as broad anti-tumor spectrum and being effective in treating hypoxic cells. However, it has toxicity to the kidneys, nervous system and pancreas. Modern pharmacology has classified this product as antineoplastic agents.
Pharmacological effects
Cisplatin is the most commonly used metal platinum complexes with the platinum atoms containing in the molecule being important for its anti tumor effect. However, it is also effective in the form of cis while being invalid in the Trans form. It can be cross-linked to DNA strand, showing cytotoxicity. After its dissolution inside the human body, it doesn’t need carrier transport in the body while being able to penetrate through the charged cell membrane. Owing to the low intracellular chloride concentration (4mmol /L), chloride ions are replaced by the water with the charge being positive which has a similar effect as bifunctional group of alkylating agent. It can combine with the nuclear DNA bases, forming three forms of cross-linking, resulting in DNA damage, further destroying DNA replication and transcription with the capability of inhibiting the synthesis of RNA and proteins at high concentrations as well. Cisplatin is characterized by broad anti-cancer spectrum, being effective in treating hypoxic cells and strong action. It has been widely used in the treatment of testicular cancer, ovarian cancer, uterine cancer, bladder cancer, cervical cancer, prostate cancer and brain cancer with significant efficacy. However, cisplatin has certain toxicity when being used in the treatment of cancer and thus being able to cause side effects. Therefore, it is necessary to continuously identify analogues of cisplatin with less toxicity and clinical effect being similar as cisplatin. So far scientists from various countries have been synthesized and tested thousands of cisplatin-related metal complexes and have developed the second-generation anti-cancer platinum complexes with carboplatin being the representative. The third generation anticancer metal complexes have also been identified with titanocene dichloride as the representative. These compounds have nothing to do with cisplatin from the chemical perspective but they have relative good efficacy in treating some kinds of cancer which can be hardly treated by cisplatin without doing harm to the kidney function. Now people in this area are continuing extensive research with the efforts majorly lining in exploring the anticancer mechanism of metal complexes at the molecular level. China has already started producing the goods of cisplatin and has carried out research in this area.
Cisplatin belongs to non-specific cell cycle drugs with cytotoxicity. Since the proliferation and synthesis rate of cancer cells is more rapid than normal cells, the cancer cell is more sensitive than normal cell to the toxic effects of this product. It can inhibit the DNA replication of cancer cell, and destroy the structure of the cell membrane. It has a strong broad-spectrum anti-cancer effect. It can be used for the treatment of ovarian cancer, prostate cancer, testicular cancer and other genitourinary malignancies with an excellent efficacy. When being used in combination with vincristine, cyclophosphamide and 5-fluorouracil, it has an excellent efficacy in the treatment of malignant lymphoma, breast cancer, carcinoma of head and neck squamous cell, thyroid cancer, and osteosarcoma, etc. Cisplatin, in combination with radiotherapy, can be used in the treatment for patients with advanced non-small cell lung cancer; nasopharyngeal cancer and esophageal cancer with prominent effect. It also has certain efficacy in the treatment of liver cancer and soft tissue sarcoma. Cisplatin, as a strong accumulative drug, is easy to produce renal toxicity with the gastrointestinal reactions being relatively common with neutropenia occurring in some patients but can be restored after the withdrawal of drugs for 7 to 14 days.
In addition, the DNA damage effect of this product can also possibly change the antigenicity in the nucleus or the cell surface so that the original hidden surface antigen is exposed, stimulating the immune suppression of antibodies and exert their cytotoxic effects.
This information is edited by Xiongfeng Dai from Chemicalbook.
Adverse reactions and side effects
Upon being subject to one-time injection of cisplatin for 50mg/m2, 25% to 30% of patients can get azotemia. Upon a larger dose and continuous medication, it can have serious and long-lasting kidney toxicity, manifested as tubular swelling, degenerative disease, elevated level of serum urea nitrogen, decreased creatinine clearance, hematuria, proteinuria, and even uremia.
It may have mild to moderate bone marrow toxicity whose degree depends on the amount of cisplatin. Anemia is common and may be accompanied with hemolysis. The patients can get severe nausea and vomiting which often appears at the beginning of treatment within 1h, lasting 8~12 h. The patients can administrate dexamethasone, ondansetron and diazepam to reduce the reaction.
It can cause malignant renal toxicity and is prone to occur at patients free from hydration and patients of diuretic therapy.
Combination with renal toxic antibiotics may increase the risk of enhancing acute renal failure.
It can commonly cause high-frequency hearing loss, and occasionally significant hearing loss. Tinnitus can occur at rare cases.
There may be significant symptoms of hyponatremia, hypomagnesemia, hypocalcemia, and hypokalemia which may occur in a few days after treatment.
After several times of administration can cause allergic reaction which can occur within minutes after administration, being manifested as facial edema, wheezing, tachycardia, etc. The patients should be quickly subject to anti-allergy measures such as antihistamine and adrenocorticotropic hormone.
There may be peripheral nerve toxicity. Hyperuricemia occurs rarely. There are occasional symptoms of orthostatic hypotension.
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
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.
Uses
cisplatin is a platinum complex, cis-[PtCl2(NH3)2], used in cancer treatmentto inhibit the growth oftumours. It acts by binding betweenstrands of DNA.
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.
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.
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.
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
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.
General Description
An anticancer drug. Orange-yellow to deep yellow solid or powder.
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.
reaction suitability
core: platinum
reagent type: catalyst
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.
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
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.
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.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)
