Oct 23, 2003 cisplatin is one of the most potent antitumor agents known, displaying clinical activity against a wide variety of solid tumors. In addition, in the cytoplasm many potential platinumbinding sites are also available, including rna and sulfurcontaining biomolecules. This project focused more on the visual, not so much on the scientific accuracy. Some centres dilute cisplatin in 500 to ml of ns, depending on the dose. Moreover, there is much evidence suggesting that the cytotoxic effects induced by binding of cisplatin to nondna targets especially proteins may contribute to its biochemical mechanism of action. Cisplatin, carboplatin, oxaliplatin cyclophosphamide, ifosfamide dacarbazine mechlorethamine nitrogen mustard melphalan nitrosoureas procarbazine streptozotocin temozolomide thiotepa mechanism of action. Cisplatin is a chemotherapeutic drug that has been used in the treatment of various types of human cancers such as ovarian, lung, head and neck, testicular and bladder.
Studying nucleotide excision repair of mammalian dna in a cell free system. Of the many potential sites available, cisplatin has been shown to selectively bind to only a few. Cisplatin, cisplatinum or cisdiamminedichloridoplatinumii cddp is a platinumbased chemotherapy drug used to treat various types of cancers, including sarcomas, some carcinomas e. Platinumbased antineoplastic drugs informally called platins are chemotherapeutic agents used to treat cancer. Cisplatin, platinumbased drugs, mechanisms of action, cancer treatment. While a combinationchemotherapy with cisplatin is a cornerstone for the treatment of multiple cancers, the challenge is that cancer cells could become cisplatin resistant. In comparison, aki induced by the cancer chemotherapeutic and prominent nephrotoxicant cisplatin also. Cisplatin has left its mark also on areas that are generally considered largely inorganic. Multiple transporters participate in the active transport of platinum. Numerous mechanisms of cisplatin resistance were described including.
Research over the past 10 years has uncovered many of the cellular mechanisms which underlie cisplatin induced renal cell death. The first step in the process after the cisplatin molecule penetrates the cell membrane intact is for a molecule of water to. To overcome resistance, cisplatin is commonly used in combination with some other drugs in treating ovarian cancer, biliary tract cancer, lung cancer diffuse malignant pleural mesothelioma, gastric cancer, carcinoma of salivary gland origin. In this form of chemotherapy, commonly used drugs include cisplatin, oxaliplatin, and carboplatin, but several have been proposed or are under development. Drug dilution and infusion durations vary according to the regimen. Once in the bloodstream, it binds strongly to plasma proteins. Despite existing toxicities, resistance associated with treatment failures, and poorly understood mechanism of action, cisplatinbased chemotherapy remains the. Inside the cell, the generally accepted major cytotoxic mechanism of action of cisplatin. These free radicals attack polyunsaturated lipids and proteins and. Oxaliplatin has a different radiosensitizing mechanism than cisplatin. The other two ligands in carboplatin are present in a ring structure rather than as two chloride atoms in cisplatin. The first step in the process after the cisplatin molecule penetrates thecell membrane intact is for a molecule of water to replace one of the chloride ions. Adverse effects profile of dicycloplatin anticancer research. Cisplatin coordinates to dna mainly through certain nitrogen atoms of the dna base pairs.
Its covalent bonds readily exchange with other ligands, including even water. After cisplatin enters the cells, the chloride ligands are replaced by water molecules. Carboplatin is a derivative of cisplatin and has a similar mechanism of action, differing only in terms of structure and toxicity. The primary dna adducts is the intrastrand crosslink adducts responsible for activation of apoptosis. It binds to the dna and this result the inhibition of dna synthesis and dna repair which activate apoptosis. Mechanism of action of cisplatin cisplatin exerts its cytotoxic effect by different ways. Cisplatin, cisplatinum or cisdiamminedichloroplatinumii cddp is a platinumbased chemotherapy drug used to treat various types of cancers, including sarcomas, some carcinomas e. 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 similar to the bifunctional alkylating agents. From the sleeping beauty it made its way to the headlines of scientific journals, thanks to a class of novel pt antitumor. Mechanism of action and pharmacokinetics indications and status adverse effects dosing. Cisplatin for injection has been administered at 75 mgm. All patients should receive adequate hydration and premedication for emesis, according to local guidelines. These drugs are used to treat almost half of people receiving chemotherapy for cancer. One of the limiting side effects of cisplatin use is nephrotoxicity. Mechanisms of action of cisplatin cisplatin is administered to cancer patients intravenously as a sterile saline solution. Cisplatin is a widely used and highly effective cancer chemotherapeutic agent. Cisplatin about cisplatin alkylating agent, platinum analog, antineoplastic.
The anticancer activity of cisplatin was discovered in the early 1960s by professor barnett rosenberg at the university of michigan rosenberg, vancamp, krigas, 1965. Synthesis, antitumour activity and mechanism of action. Jul 29, 20 the mechanism of action and toxicities of different chemotherapeutic agents are discrete and while it may be that some of the doxorubicin effect on the growing follicle pool is due to a cytotoxic effect on the dividing granulosa cells, our data suggest this is not the cause of cisplatin induced damage. 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. Its mode of action is linked to the ability of cisplatin to interact with purine bases on the dna, causing dna. One clue to the mechanisms of action arose from studies of the biosynthesis in both normal and cancerous tissues, both in vitro and in vivo harder and rosenberg, 1970. Pdf possible incorporation of free n7 platinated guanines. Molecular mechanism of cisplatin resistance request pdf. Actl6a promotes repair of cisplatininduced dna damage, a. Cisplatin is physically incompatible with any iv set, needle or syringe containing aluminum. A systems biology approach to understanding the mechanisms of. Cisplatin and doxorubicin induce distinct mechanisms of.
This reaction results in the formation of positively charged platinum complexes that react with the nucleophilic sites on dna. Platinum complexes are clinically used as adjuvant therapy of cancers aiming to induce tumor cell death. The mechanisms mediating renal cell death induced by nephrotoxicants and renal pathologies are strikingly similar. Other mechanisms of cisplatin cytotoxicity include mitochondrial damage, decreased atpase activity, and altered cellular transport mechanisms. Eribulin nontaxane tubulin binding agent a marine sponge product. Frontiers cisplatinmembrane interactions and their. Jan 19, 2021 actl6a is a subunit shared by multiple complexes, including swisnf, ino80, and nua4tip60. This reaction results in the formation of positively charged platinum complexes that react with the nucleophilic. Since the beginning of cisplatin related research, strong efforts have been made to rationalize the mechanism of action and the drug design. We also show that the action of actl6a in the repair of cisplatin induced dna lesions is through the swisnf remodeling complex. Pt radiosensitizers, radiochemotherapy mechanisms, free. Enhancement of excision repair of cisplatindna adducts.
Comparative study of the mode of action of clinically. The detailed mechanism by which cisplatin kills cancer cells is still being actively studied, but apoptosis appears to play a central role. The mechanism of action of cisplatin has been associated with ability to crosslink with the urine bases on the dna to form dna adducts, preventing repair of the dna leading. This suggests that different mechanisms of action are at play for each of the. New insights into mechanisms of cisplatin resistance. While considered cell cycle nonspecific, cytotoxicity is increased with exposure during the sphase. However, the intrinsic or acquired resistance severely limit the clinical application of platinumbased treatment. Depending on cell type and concentration, cisplatin induces cytotoxicity, e. Introductionbiochemical modulation is the manipulation of cellular biochemical pathways by chemical agents to produce selective enhancement of the efficacy of an antitumor drug. The subject of mixedvalance pt compounds is an example. Pdf biochemical modulation of cisplatin mechanisms of.
Similarly, the addition of cisplatin to adjuvant chemotherapy led to a marked increase in disease free survival rates for patients with medulloblastoma again, up to around 85%. Bind to microtubular proteins, thus inhibit micro tubule assembly resulting in dissolution of the mitotic assembly structure. Dec 17, 2020 cisplatin inhibits dna and rna synthesis by prokaryotic and eukaryotic dna and rna polymerases, respectively both in vitro and in vivo. Target dna, produce alkylation through formation of. Vecchio, alessandro romano, tiziano verri, and francesco p. Frontiers the drugresistance mechanisms of five platinum. We unveil a new role for actl6a in repairing cisplatin induced dna damage, providing a novel mechanism for cisplatin resistance.
Cisplatin for injection has been administered at 50 mgm. Special attention is given to the synthesis of the compound and re. Additionally, cisplatin damages tumors via induction of apoptosis, mediated by the. Pdf platinum complexes are clinically used as adjuvant therapy of cancers aiming to induce tumor cell death. 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 dna damage response and the induction of mitochondrial apoptosis. Actl6a promotes repair of cisplatininduced dna damage, a new. First, a single damaged rna molecule can be replaced by newly synthesized material. Other doses and combination regimens have been used. Cisplatin exerts anticancer effects via multiple mechanisms, yet its most prominent and best understood mode of action involves the.
Treatment of cervical cancer with a conjunction of cisplatin and ionizing radiation increased survival and disease free intervals and became a part of standard care. Cancers free fulltext cisplatin as an antitumor drug. Pdf although cisplatin, cisdiamminedichloroplatinumii, has been successfully used in the chemotherapy of cancer for more than 25 years, its. 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 involving atr, p53, p73, and mapk, and culminate in the activation. The current accepted paradigm about cisplatin mechanism of action is that. Initially, it was reported that o 6guanine atom six of guanine, was the site of importance, being linked with both carcinogenesis and the mechanism of antitumour action. Jan 01, 1980 therefore, selective cancer killing must be due to the different ways that cancer cells and normal cells process the cisplatin lesions.
Cisplatin causes cell cycle arrest in the g2phase and then induces programmed cell death or apoptosis. The ammine groups represent carrier ligands, while chloride ions are leaving groups. In contrast to cisplatin, the different mechanisms of action that are indicated for 56mess suggest that this compound could overcome cisplatin resistance either as a standalone treatment or a synergistic component of therapeutics. Resistance is a significant problem with cisplatin treatment. Oct 05, 2014 the proposed mechanisms of cisplatin resistance include changes in cellular uptake and efflux of cisplatin, increased biotransformation and detoxification in the liver, and increase in dna repair and antiapoptotic mechanisms gottesman et al. A special attention is paid to its molecular mechanisms of action, and its undesirable side effects. In the circulation, chloride concentration is relatively high and cisplatin remains neutral and can be transported throughout the body. 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. Much is now understood as to how tumours all too commonly exhibit resistance to cisplatin, either intrinsically or as acquired during courses of therapy. Its history and possible mechanisms of action 3 effects of cisplatin on dna and the possible relationships to cytotoxicity and mutagenicity in mammalian cells 4 the lethal activity of platinum compounds in combination with pyrimidine derivatives 5 repair of cisplatin induced dna damage and cell sensitivity. Molecular mechanisms of cisplatin resistance oncogene nature. Possible incorporation of free n7platinated guanines in dna by dna polymerases, relevance for the cisplatin mechanism of action michele benedetti, cosimo ducani, danilo migoni, daniela antonucci, vita m.
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. The current accepted paradigm about cisplatin mechanism of action is that the. It covalently binds to dna and disrupts dna function. Cisplatin is an effective chemotherapeutic agent commonly used in the treatment of malignant tumours, but ototoxicity is a significant side effect. The biochemical mechanisms of cisplatin cytotoxicity involve the binding of the drug to dna and nondna targets and the subsequent induction of cell death through apoptosis, necrosis, or both. Jul 12, 2007 the mechanism of action of cisplatin and carboplatin involves covalent binding to purine dna bases, which primarily leads to cellular apoptosis. Identification name cisplatin accession number db00515 description. Definitive information about the mechanism of action of cisplatin includes four key steps. Fanizzi abstract cisplatin, cisdiamminedichloroplatinum ii, is one of the most widely used anticancer drugs. The possible mechanism of anticancer action of cisplatin is associated with its ability to interact. Cisplatin is one of the most potent antitumor agents known, displaying clinical activity against a wide variety of solid tumors. Like cisplatin, it contains a platinum atom surrounded in a plane by two ammonia groups and two other ligands in the cis position. 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. The shape of the cisplatin molecule is square and flat.
Cellular and molecular pharmacology of oxaliplatin1. Cisplatin has demonstrated efficacy against various types of cancers such as germ cell tumors, sarcomas, carcinomas as well as lymphomas. It was the first member of its class, which now also includes carboplatin and. The underlying mechanisms are incredibly complicated. Additionally, cisplatin damages tumors via induction of apoptosis, mediated by the activation of various signal transduction pathways. Cisplatin, cancer, molecular and immunomodulatory effects, genes. The possible mechanism of anticancer action of cisplatin is associated with its ability to interact with dna, denature the double helix, inhibit the repair of dna and induce apoptosis in tumor. Because the principal action mechanism of cddp cytotoxicity is the formation of. Molecular mechanisms of cisplatin resistance oncogene. To discuss the mechanisms of cisplatin ototoxicity and subsequent cell death, and to present the results of experimental studies. Its cytotoxic mode of action is mediated by its interaction with.
The principle of action 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. The mechanism of action of cisplatin involves covalent binding to purine dna bases, which primarily leads to dna damage, dna repair and cellular apoptosis 6 7 8. Mechanisms of action of cisplatin in cancer cells bound to two ammine groups and two chloride ions that are arranged in a square fig. Cisplatin s action inside the cell is familiar to anyone who took organic chemistry in college. Mar 20, 2020 platinumbased anticancer drugs, including cisplatin, carboplatin, oxaliplatin, nedaplatin, and lobaplatin, are heavily applied in chemotherapy regimens. Accumulation of free ultrafilterable platinum in plasma can potentially occur when cisplatin is administered on a daily basis. These showed that exposure to the equivalent of therapeutic doses of cisplatin selectively and persistently inhibits new dna synthesis, with little or no concomitant. Chemical properties and mechanism of action for cisplatin.
Platinum has been detected in many tissues for up to 6. For example, ischemiainduced aki involves atp depletion, oxidative stress, proximal tubule cell death and loss of the brush border membrane, and cell polarity devarajan, 2006. 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 particularly effective against testicular cancer. Cisplatin cisplatin dose, indications, adverse effects.
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