Molecular mechanisms of cisplatininduced nephrotoxicity. Cisplatin annals of internal medicine american college. Mechanism of action and pharmacokinetics indications and status adverse effects dosing administration guidelines special precautions interactions recommended clinical monitoring supplementary public funding references disclaimer. The mode of action of pt and pdbased anticancer agents cisplatin and pd2spm was studied by characterising their impact on dna. The primary mechanism by which they exert their action is through the formation of adducts with genomic dna. Although cisplatin can coordinate to rna, this interaction is not believed to play an important role in cisplatin s mechanism of action in the body for two reasons. Cisplatin is believed to kill cancer cells by binding to dna and interfering with its repair mechanism, eventually leading to cell death.
The principle of action of cisplatin in combating cancer involves exerting its cytotoxicity upon cancer cells through the formation of dna adducts that include mono, inter, and intrastrand cisplatin dna crosslinks that arrest the cell cycle at s, g1 or g2m thus induces apoptosis. Whereas the general mode of action is agreed upon, many details about how cisplatin interacts with its cellular target, genomic dna, remain poorly understood. Cisplatin is stable under normal temperatures and pressures, but may transform slowly over time to the transisomer iarc 1981, akron 2009. Cisplatin has demonstrated efficacy against various types of cancers such as germ cell tumors, sarcomas, carcinomas as well as lymphomas. There are many options to help minimize or prevent the side effects of cisplatin. Feb 26, 2019 carboplatin is one of the platinumbased anticancer drugs and its parent compound is cisplatin. See chemotherapy nephrotoxicity and dose modification in patients with renal insufficiency. Medlineplus information on cisplatin a lay language summary of important information about this drug that may include the following.
Its mode of action is linked to the ability of cisplatin to interact with purine bases on the dna. Its cytotoxic mode of action is mediated by its interaction with dna to form dna adducts, primarily intrastrand crosslink adducts, which activate several signal transduction pathways, including those. Its mode of action has been linked to its ability to crosslink with the. Cisplatin combination chemotherapy is the cornerstone of treatment of many cancers. Cisplatin is stable under normal temperatures and pressures, but may transform slowly over time to the transisomer iarc, 1981, akron, 2009. Its cytotoxic mode of action is mediated by its interaction with dna to form dna adducts, primarily intrastrand crosslink adducts, which activate. Cisplatin fda prescribing information, side effects and uses. Oct 05, 2014 cisplatin has a molecular weight of 301. Computational studies can offer valuable insights and possibly provide a foundation for new strategies.
Cisplatin for injection is a highly emetogenic antineoplastic agent. Synthesis, antitumour activity and mechanism of action. Cisplatin is a member of the alkylating agents drug class and is commonly used for anal cancer, bladder cancer, blood cell transplantation, and others. Molecular mechanisms of cisplatin resistance nature. Cisplatin and other platinumii analogs are widely used in clinical practice as anticancer drugs for a wide range of tumors. The major mapk subfamily members include the extracellular signalregulated kinases erk, the cjun nterminal kinases jnks, also referred to as stressactivated protein kinase sapk, and the p38 kinases. Definition from the nci drug dictionary detailed scientific definition and other names for this drug. Cisplatin is one of the most widely used and most potent chemotherapy drugs. This cisplatin price guide is based on using the discount card which is accepted at most u.
Research over the past 10 years has uncovered many of the cellular mechanisms which underlie cisplatin induced renal cell death. Cisplatin, platinumbased drugs, mechanisms of action, cancer treatment. Cisplatin side effects will improve after therapy is complete. The cytotoxic activity of cisplatin may arise from the cells inability to repair dna damage caused by cisplatin.
Each vial of platinol contains 50 mg cisplatin, 450 mg sodium chloride, usp, and 500 mg mannitol, usp. Peyrone in 1844 and its chemical structure was first elucidated by alfred werner in 1893. Variations in the dosage and mode of administration as well as development of cisplatin analogues are being currently studied. It covalently binds to dna and disrupts dna function. The drugs mode of action is binding to the dna in the tumor cells, where it distorts the dna structure and ultimately triggers cell death. Cisplatin is a cancer medication that interferes with the growth of cancer cells and slows their growth and spread in the body. The involvement of the mapk pathway in cisplatins mode of action is of significant interest. Indeed, in vitro studies on cell extracts suggest that the most common cisplatindna adducts that is, 1,2intrastrand adducts are not readily repaired by the excision repair system see dna module. Numerous mechanisms of cisplatin resistance were described including. More recent clinical studies of cisplatin have shown a broad range of activity and provide a better understanding of the drugs pharmacology, mechanism of action, and toxicity. Anderson cancer center, 1515 holcombe boulevard, houston, tx 770304009, usa cisplatin is one of the most potent antitumor agents.
Mechanism of action cisplatin is believed to kill cancer cells by binding to dna and interfering with its repair mechanism, eventually leading to cell death. Cisplatin is particularly effective against testicular cancer. Since the discovery by rosenberg and collaborators of the antitumor activity of cisplatin 35 years ago, three platinum antitumor drugs cisplatin, carboplatin and oxaliplatin have enjoyed a huge clinical and commercial hit. Interaction with cellular proteins, particularly hmg domain proteins, has also been advanced as a mechanism of interfering with mitosis, although this is probably not its primary method of action. Its cytotoxic mode of action is mediated by its interaction with. The mechanism of action of cisplatin has been associated with ability to crosslink with the urine bases on the dna to form dna adducts. Cisplatin is also being studied in the treatment of other types of cancer.
If you continue browsing the site, you agree to the use of cookies on this website. Cisplatin is similar to the bifunctional alkylating agents. Frontiers cisplatinmembrane interactions and their. Cisplatin has left its mark also on areas that are generally considered largely inorganic. A further feature of treatment with cisplatin is the marked synergy shown in combination with a wide variety of other chemotherapeutic agents, such as 5fluorouracil, cytarabine and bleomycin, which, on a practical level, allows for greater flexibility in the design of drug regimens. Cisplatin may decrease the excretion rate of lithium carbonate which could result in a higher serum level. Marques,ab diego gianolio,c giannantonio cibin,c john tomkinson,d. Cisplatin is used together with other medications to treat bladder cancer, testicular cancer, or ovarian cancer cisplatin may also be used for purposes not listed in this medication guide.
Cisplatin cisdiamminedichloroplatinum ii, cddp is one of the most effective chemotherapeutic agents. A new look into the mode of action of metalbased anticancer. Cisplatin exerts anticancer effects via multiple mechanisms, yet its most prominent and best understood mode of action involves the generation of dna lesions followed by the activation of the. One of the limiting side effects of cisplatin use is nephrotoxicity. It was approved by the fda in the 1980s and since then it has been widely used in the treatment of several tumor types.
Singledrug therapy can attack several cellular targets using. Cisplatin is in a class of drugs known as platinumcontaining compounds used to treat various types of cancers including metastatic testicular and ovarian tumors. Indeed, cisplatin is one of the most successful anticancer agents, effective against a wide range of solid tumors. First, a single damaged rna molecule can be replaced by newly synthesized material. Cisplatin dosing, indications, interactions, adverse effects. Platinol cisplatin for injection, usp should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Special attention is given to the synthesis of the compound and related derivatives, and to the nature of the hydrolysis products in blood and in the cell.
From the sleeping beauty it made its way to the headlines of scientific journals, thanks to a class of novel pt antitumor agents, the socalled platinum pyrimidine blues. Moreover, the binding of cisplatin to proteins and enzymes may modulate its biochemical mechanism of action. Inside the cell, the chloride atoms of cisplatin may be displaced and the compound may be inactivated directly by reaction with nucleophiles such as thiols. The immunogenic effects of platinumbased chemotherapeutics stanleyson v. Cisplatin exerts anticancer effects via multiple mechanisms, yet its most prominent and best understood mode of action involves. After cisplatin enters the cells, the chloride ligands are replaced by water molecules. The most frequently clinically applied chemotherapeutic drug is cisplatin, a metal complex based on the platinumii ion. Cisplatin is a widely used and highly effective cancer chemotherapeutic agent. Marques, ab diego gianolio, c giannantonio cibin, c john tomkinson, d stewart f. Mechanisms of cisplatininduced apoptosis and of cisplatin. Cisplatin, cis ptcl 2 nh 3 2, is extensively used for the treatment of testicular and ovarian cancers and increasingly against other types of solid tumours headneck, lung, cervical, and bladder, and gives a greater than 90% cure rate in the case of testicular cancer. Recent research has shed significant new lights on the mechanism of cisplatin nephrotoxicity, especially on the signaling pathways leading to tubular cell death. Other chemicals facilitate the interaction of cisplatin with dna, and they are often combined with cisplatin for chemotherapy. Jul 20, 2018 how does cisplatin work to treat cancer.
Cisplatin annals of internal medicine american college of. We propose here a new mechanism of cisplatin resistance mediated by glutathione transferase gst p11, as a cisplatin binding protein. The subject of mixedvalance pt compounds is an example. Recent research has shed significant new lights on the mechanism of cisplatin nephrotoxicity, especially on the signaling pathways. The activated cisplatin then binds primarily at the n7 positions of guanine and adenine of dna, rna, and macromolecules resulting from attractive binding properties of the imidazole ring. Cisplatin prices, coupons and patient assistance programs. A structurebased mechanism of cisplatin resistance. Carboplatin is a cisplatin analogue that also induces dna adduct formation and interstrand crosslinking. Cisplatin is used in combination with other chemical agents or compounds to treat ovarian cancer in both the resistant and sensitive cell lines. The first step in the process after the cisplatin molecule penetrates the cell membrane intact is for a molecule of water to replace one of the chloride ions. Cisplatin side effects are often predictable in terms of their onset, duration, and severity.
However, its clinical use is limited due to the severe side effects, including nephrotoxicity and acute kidney injury aki which develop due to renal accumulation and biotransformation of cddp. Joost lesterhuis3 abstract the platinumbased drugs cisplatin, carboplatin, and oxaliplatin belong to the most widely used che. While a combinationchemotherapy with cisplatin is a cornerstone for the treatment of multiple cancers, the challenge is that cancer cells could become cisplatin resistant. Cisplatin may decrease the excretion rate of lithium cation which could result in a higher serum level. The mode of action of pt and pdbased anticancer agents cisplatin and pd2spm was studied by. Cisplatin is one of the most potent antitumor agents known, displaying clinical activity against a wide variety of solid tumors.
The alleviation or prevention of cddpcaused nephrotoxicity is. Biochemical mechanisms of cisplatin cytotoxicity bentham. This reaction results in the formation of positively charged platinum complexes that react with the nucleophilic. Because of the relatively low compared with the extracellular microenvironment concentration of chloride ions, intracellular cisplatin quickly becomes aquated and. Mar 25, 2009 cisplatin is in a class of drugs known as platinumcontaining compounds used to treat various types of cancers including metastatic testicular and ovarian tumors. However, the mechanism by which these adducts kill cells is less well understood.
The use of cisplatin in patients with preexisting renal dysfunction and the renal effects of the platinum analogs, carboplatin and oxaliplatin, are discussed elsewhere. Molecular mechanisms of cisplatin resistance oncogene. The main mechanism of the cytotoxic action involves the binding of cisplatin to genomic dna in the cell nucleus to form interstrand and intrastrand crosslinks. Cisplatin may decrease the excretion rate of lithium citrate which could result in a higher serum level. Changes in conformation and mobility at the molecular level in hydrated dna were analysed by quasielastic and inelastic neutron scattering techniques qens and ins, coupled to fourier transform infrared ftir and microraman spectroscopies. Although cisplatin, cisdiamminedichloroplatinumii, has been successfully used in the chemotherapy of cancer for more than 25 years, its biochemical mechanism of action is still unclear. Cisplatin is the most important and efficacious chemotherapeutic agent for the treatment of advanced gastric cancer. However, side effects in normal tissues and organs, notably nephrotoxicity in the kidneys, limit the use of cisplatin and related platinumbased therapeutics. The current accepted paradigm about cisplatin mechanism of action is that. Cisplatin clinical pharmacology mechanism of action. Cisplatin forms inter and intrastrand crosslinked dna adducts and its cytotoxicity is mediated by propagation of dna damage recognition signals to downstream pathways involving atr, p53, p73, and mitogenactivated protein kinases, ultimately resulting in apoptosis. We think that the study of the molecular determinants involved in the mechanism of action of cisplatin and its analogs is an extremely important interdisciplinary field that requires the collaboration of chemists, biologists, pharmacologists, and physicians who, in some cases, do not always communicate on the same level. The current accepted paradigm about cisplatin mechanism of action is that the drug induces its cytotoxic properties through binding to nuclear dna and subsequent interference.
Despite a similar mechanism of action to cisplatin, the toxicity profile is significantly different, with myelosuppression being the doselimiting toxicity. Carboplatin has gained significant popularity since its introduction in the 1980s because it causes. Ever since the initial discovery of the anticancer. Cisplatin passively enters the cells where it is activated into an electrophile by replacing two chloride groups with hydroxyl or water. Cisplatin has a number of side effects that can limit its use. Cisplatin terry clayton biological inorganic chemistry april 1, 2007 slideshare uses cookies to improve functionality and performance, and to provide you with relevant advertising. The active ingredient, cisplatin, is a yellow to orange crystalline powder with the molecular formula ptcl 2 h 6 n 2, and a molecular weight of 300. However, its use is restricted by side effects andor by intrinsic or acquired drug resistance. Oct 23, 2003 cisplatin is one of the most potent antitumor agents known, displaying clinical activity against a wide variety of solid tumors. However, multiple cellular targets by platinumii complexes have been described. Appropriate management of therapy and complications is possible only when adequate. Cisplatin derivatives are used as the mainline treatment of ovarian cancer, despite their severe side effects and development of resistance. Cisplatin dosing, indications, interactions, adverse. The knowledge of mechanism of action of these drugs reveals mechanisms of resistance and toxicity.
1299 1126 1373 301 1462 378 936 1023 1072 893 1049 795 1358 676 1223 1338 665 1397 1398 1504 144 1493 1280 647 28 257 81 1370 1483 1129 1330 208 346 143 738 1084