New insights into mechanisms of cisplatin resistance. Cisplatin about cisplatin alkylating agent, platinum analog, antineoplastic. Slow infusion of the drug 24 hr also appears to mitigate these effects. 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. Cisplatin for injection is a highly emetogenic antineoplastic agent.
Mechanism of action of cisplatin cisplatin exerts its cytotoxic effect by different ways. In the circulation, chloride concentration is relatively high and cisplatin remains neutral and can be transported throughout the body. 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. Numerous mechanisms of cisplatin resistance were described including. 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. Discovery of cisplatin mechanism of action activity. To overcome resistance, cisplatin is commonly used in combination with some other drugs in. How cells respond to cisplatin induced dna damage plays a critical role in deciding cisplatin sensitivity. Chinese scientists recently found that cisplatin induced loop structures and condensation in the dna. Mechanism and reversal of druginduced nephrotoxicity on a. Its mode of action is linked to the ability of cisplatin to interact with purine bases. Mar 06, 2010 cytotoxicity cisplatin resistant tumor lines ic 50 m cancer cell line cisplatin 1 chronic myelogenous leukemia k562 80 3 chronic myelogenous leukemia kg1 48 2 acute myelogenous leukemia ml2 80 1 mouse melanoma b16 80 6 colon cancer ht29n 80 12 colon cancer ht29 50 8 colon cancer hct116 80 9 lung carcinoma a427 63 6 breast carcinoma. Jun 09, 2007 the cytotoxicity of cisplatin as a very effective chemotherapeutic anticancer drug is known to arise from its capacity to damage dna. Other doses and combination regimens have been used.
Molecular mechanisms of cisplatin resistance oncogene. 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. The initial physisorption of cisplatin into the polar region of the lipid membrane is controlled, in a first moment, by long. Mar, 2019 background cisplatin cisdiamminedichloroplatinum ii, cddp is one of the most effective chemotherapeutic agents. The mechanism of action of cisplatin has been associated with ability to crosslink with the urine bases on the dna to. Once in the bloodstream, it binds strongly to plasma proteins. Cisplatin for injection is a platinumbased drug indicated for the treatment of.
Cisplatin is a widely used and highly effective cancer chemotherapeutic agent. Cisplatin and other platinum derivatives are the most widely used chemotherapeutic agents to treat solid tumors including ovarian, head and neck, and testicular germ cell tumors. Cisplatin dosing, indications, interactions, adverse. As studied mainly on cisplatin, but presumably for other members as well, platinumbased antineoplastic agents cause crosslinking of dna as monoadduct, interstrand crosslinks, intrastrand crosslinks or dna protein crosslinks. Cisplatin induced dna damage activates various signaling pathways to. Actl6a promotes repair of cisplatininduced dna damage, a. Research over the past 10 years has uncovered many of the cellular mechanisms which underlie cisplatin induced renal cell death. Mechanisms of action of cisplatin cisplatin is administered to cancer patients intravenously as a sterile saline solution. Because the principal action mechanism of cddp cytotoxicity is the formation. This suggests that different mechanisms of action are at play for each of the.
Cisplatin for injection has been administered at 50 mgm. One of the limiting side effects of cisplatin use is nephrotoxicity. Many mechanisms of cisplatin resistance have been proposed including. Dec 17, 2020 the limitations of using cisplatin in cancer chemotherapy are also associated with intrinsic and acquired resistance of tumor cells to this drug. After cisplatin enters the cells, the chloride ligands are replaced by water molecules. Molecular mechanisms of cisplatininduced nephrotoxicity. It covalently binds to dna and disrupts dna function. 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. The term alkylating derives from the drugs mechanism of action.
It is generally believed that the nausea and vomiting arise from the action of the drug on the. 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. We also show that the action of actl6a in the repair of cisplatin induced dna lesions is through the swisnf remodeling complex. Cisplatin is administered intravenously as shortterm infusion in normal saline for treatment of solid and haematological malignancies. Satraplatin inn, codenamed jm216 is a platinumbased antineoplastic agent that was under investigation as a treatment of patients with advanced prostate cancer who have failed previous chemotherapy. Mechanism of action and pharmacokinetics indications and status adverse effects dosing administration guidelines. Since the beginning of cisplatin related research, strong efforts have been made to rationalize the mechanism of action and the drug design.
Cisplatin dosing, indications, interactions, adverse effects. Investigating the chemotherapeutic mechanism of action of cisplatin 9783845415185. The current accepted paradigm about cisplatin mechanism of action is that the drug induces its cytotoxic properties through binding to nuclear dna and. This paper summarizes our current understandings regarding the mechanisms by which cisplatin induces cell death and the bases of cisplatin resistance. First, a single damaged rna molecule can be replaced by newly synthesized material.
B mechanism of action and pharmacokinetics cisplatin is biochemically similar to bifunctional alkylating agents as it inhibits dna synthesis through covalent binding leading to intrastrand, interstrand, and protein crosslinking causing apoptosis. Jul 29, 20 cisplatin is a dna crosslinking agent commonly used in the treatment of sarcomas and germ cell tumours. The dnadamaging compound, cisplatin cisdiamminedichloridoplatinum ii, is a highly successful antitumour agent widely used in the treatment of a range of human cancers. Cisplatin has demonstrated efficacy against various types of cancers such as germ cell tumors, sarcomas, carcinomas as well as lymphomas. Definitive information about the mechanism of action of cisplatin includes four key steps.
Other mechanisms of cisplatin cytotoxicity include mitochondrial damage, decreased atpase activity, and altered cellular transport mechanisms. Moreover, the binding of cisplatin to proteins and enzymes may modulate its biochemical mechanism of action. The first step in the process after the cisplatin molecule penetrates the cell membrane intact is for a molecule of water to. Oct 23, 2003 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 currently accomplished. However, the mechanism by which these adducts kill cells is less well understood.
Mechanism of action and pharmacokinetics indications and status adverse effects dosing administration guidelines special precautions interactions recommended clinical monitoring supplementary public funding references disclaimer. This project focused more on the visual, not so much on the scientific accuracy. It is given by injection into a vein common side effects include bone marrow suppression, hearing problems, kidney damage. 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. At an equitoxic dose of cisplatin versus oxaliplatin or carboplatin, the level of dna adduct formation is 10 times higher with cisplatin, suggesting that a mechanism other than dna adduct formation may be. We have simulated the permeation of cisplatin through a model membrane composed of 1,2. Cisplatin causes cell cycle arrest in the g2phase and then induces programmed cell death or apoptosis. We unveil a new role for actl6a in repairing cisplatin induced dna damage, providing a novel mechanism for cisplatin resistance.
Sep 05, 2011 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. 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. Pdf biochemical modulation of cisplatin mechanisms of. Binding of cisplatin to nondna targets been reported that in the same population of cis one aspect of the biochemical mechanism of action platintreated cells, necrotic and apoptotic cell death of cisplatin that has been very little studied is the may take place together. However, the mechanism of action of cisplatin at the molecular level, in particular, the reaction dynamics of cisplatin with dna, remains elusive, and the reason why cisplatin binds to the guanine bases rather than to sdonor ligands available in cells remains a. Mechanisms that inhibit propagation of the dna damage signal to the. The current accepted paradigm about cisplatin mechanism of action is that. Cisplatin binds to the n7 reactive center on purine residues and as such can cause deoxyribonucleic acid dna damage in cancer cells. A special attention is paid to its molecular mechanisms of action, and its undesirable side effects. The nephrotoxic effect of cisplatin is cumulative and dosedependent and often necessitates dose reduction or withdrawal. Cisplatin is one of the most potent antitumor agents known, displaying clinical activity against a wide variety of solid tumors.
This was attributed to the dnas thermal fluctuation. It is generally considered as a cytotoxic drug which kills cancer cells by damaging dna and inhibiting dna synthesis. Cisplatin, cisplatinum or cisdiamminedichloroplatinumii cddp is a platinumbased chemotherapy drug used to treat various types of cancers, including sarcomas, some carcinomas e. Introductionbiochemical modulation is the manipulation of cellular biochemical pathways by chemical agents to produce selective enhancement of the efficacy of an antitumor drug. It is used to treat various types of cancers, including sarcomas, some carcinomas e. The permeation mechanism of cisplatin through a dioleoylphosphocholine bilayer. Its cytotoxic mode of action is mediated by its interaction with. This reaction results in the formation of positively charged platinum complexes that react with the nucleophilic. Target dna, produce alkylation through formation of.
Cisplatin cisplatin dose, indications, adverse effects. These include testicular cancer, ovarian cancer, cervical cancer, breast cancer, bladder cancer, head and neck cancer, esophageal cancer, lung cancer, mesothelioma, brain tumors and neuroblastoma. Cisplatin fda prescribing information, side effects and uses. Cisplatin is one of the most effective anticancer agents widely used in the treatment of solid tumors.
Pathophysiology of cisplatininduced acute kidney injury. Investigating the chemotherapeutic mechanism of action of. While a combinationchemotherapy with cisplatin is a cornerstone for the treatment of multiple cancers, the challenge is that cancer cells could become cisplatin resistant. To discuss the mechanisms of cisplatin ototoxicity and subsequent cell death, and to present the results of experimental studies. Cisplatin, carboplatin, oxaliplatin cyclophosphamide, ifosfamide dacarbazine mechlorethamine nitrogen mustard melphalan nitrosoureas procarbazine streptozotocin temozolomide thiotepa mechanism of action. A known complication of cisplatin administration is acute kidney injury aki.
Cisplatin is similar to the bifunctional alkylating agents. Its mode of action is linked to the ability of cisplatin to interact with purine bases on the dna, causing dna damage, interfering with dna repair mechanisms and. Of the covalently bound platinum in a cell, only 5% to 10% is bound to dna 14. Cisplatin is an effective chemotherapeutic agent commonly used in the treatment of malignant tumours, but ototoxicity is a significant side effect. Carboplatin and cisplatin appear to share the same mechanism of action, which involves binding of aquat. Its precise mechanism of action is not entirely clear, although it is known to intercalate with dna strands causing crosslinking and adduct formation. Its mechanism of action is through binding within and between dna strands, thereby inhibiting protein synthesis in a cell cycle phasenonspecific manner. We have discussed various steps, including the entry of cisplatin inside cells, dna repair, drug detoxification, dna damage response, and regulation of cisplatin induced apoptosis by protein kinases. Cisplatin is a chemotherapy medication used to treat a number of cancers. 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 to dna damage and subsequently induces apoptosis within cancer cells. It binds to the dna and this result the inhibition of dna synthesis and dna repair which activate apoptosis. Cisplatin and doxorubicin induce distinct mechanisms of. While considered cell cycle nonspecific, cytotoxicity is increased with exposure during the sphase. First mentioned in the medical literature in 1993, satraplatin is the first orally active platinumbased.
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