Such cellular processing eventually leads to an inhibition of the. Jul 24, 2012 the activity of platinum drugs against cancer is mediated by a combination of processes, including cell entry, drug activation, dna binding, and transcription inhibition 1. We work hard to find you the lowest prices possible without sacrificing quality. Be sure to verify your new user account in the next 24 hours, by checking your email and clicking the verify link. Despite an expanding panel of pt drugs, tumor cell. Mar 15, 2010 the anticancer activity of cisplatin and other platinum drugs is believed to arise from their interaction with dna. Mar 24, 2005 platinumdna adducts, which are formed following uptake of the drug into the nucleus of cells, activate several cellular processes that mediate the cytotoxicity of these platinum drugs. Chemistry and molecular biology of platinum anticancer drugs 733 properties of dna fundamental building blocks dna is a polymer composed of a deoxyribose sugarphosphate backbone and four nucleotide bases fig. Cancer refers to any one of a large number of diseases characterized. Cellular processing of platinum anticancer drugs nature. Despite its widespread use, we lack a comprehensive picture of global drug.
Despite the pervasiveness of platinum drugs in cancer treatment regimens. Herein, we obtained seven potential parpi with structural diversity and then conjugated them with cisplatinbased platinum iv complexes. Cisplatin is a platinum based drug that has been in widespread use for many years to treat several forms of cancer, including testicular, ovarian, cervical, head and neck, and nonsmall cell lung. Cancer cells have lost the normal regulatory mechanisms that control cell growth and multiplication.
Photoactivated platinumbased anticancer drugs sciencedirect. Jan 31, 2011 cisplatin, cisdiamminedichloroplatinumii, is widely used and among the most effective cancer chemotherapy drugs used to treat various types of cancers including sarcomas, small cell lung cancer, ovarian cancer, lymphomas, and germ cell tumors. The complexes that illustrate the prominent strategies utilized in the development of. Cisplatin in anticancer drugs free download as powerpoint presentation. Phenanthriplatin, a monofunctional dnabinding platinum. Prior to the mid 1960s, all of the drugs used for treating cancer were purely organic compounds, but the serendipitous discovery of the anticancer properties of a simple coordination compound, that later became known as cisplatin, opened new possibilities for cancer chemotherapy. Jan 27, 2016 platinum complexes which are most studied metal complexes due to their importance as adjuvant therapy of cancers aiming to induce tumorcelldeath.
Relative differences in influx and efflux contribute to drug resistance and are a primary factor in the differential response of various tumor types to the drugs 8, 9. Platinum dna adducts activate several cellular processes that are responsible for the cytotoxicity of the drug. The platinumii complexes whose structure follows these rules represent the socalled classical platinum chemotherapeutics. Platinum based anticancer agents have been widely used in the clinic to successfully treat many different types of cancer. In addition, there are a number of drugs that do not fall within. The cellular target of the three fdaapproved platinum drugs, as well as many related compounds that have been investigated, is nuclear dna. Taxanes can decrease the formation of platinumdna adducts, while topoisomerase i inhibitors enhance the number of adducts crul. Phorbiplatin, a highly potent ptiv antitumor prodrug. Synthesis of new platinumbased anticancer drugs yasser saud. The prodrug shows significant antitumor activity both in. Novel silverplatinum nanoparticles for anticancer and. The cellular uptake of phenanthriplatin is substantially.
Cisplatin is administered intravenously as shortterm infusion in normal saline for treatment of solid and haematological malignancies. Platinum anticancer drugs since cisplatin, the first fda approved ptii anticancer drug, went on the market in 1978, platinum anticancer drugs have been a great success. Current status of platinumbased antitumor drugs chemical. This article has been saved into your user account, in the favorites area, under the new folder. Wang d, lippard sjcellular processing of platinum anticancer. Platinum anticancer drugs, chemical biology of chemical. Wang d, lippard sjcellular processing of platinum anticancer drugs. Some of the platinumbased antitumor drugs like cisplatin, carboplatin and oxaliplatin, have several disadvantages including side effects, cisplatinresistant tumors, limited solubility in aqueous media, and so on. Application of fluorescence microscopy for investigation. Synthesis, cytotoxicity, and mechanistic investigation of.
Cellbased assays reveal altered cellular uptake properties and a cancer cellkilling profile different from those of established platinum drugs. Cellular rna targeting by platinum ii anticancer therapeutics cisdiamminedichloroplatinum ii, or cisplatin, is a widely prescribed anticancer compound, currently one of only three platinum ii complexes fda approved for cancer treatment. Numerous investigations have been conducted in order to determine the mechanism by which these drugs carry out their anticancer action 17 and most results concerns cisplatin. This affords primarily 1,2 or 1,3intrastrand crosslinks and a low number of interstrand crosslinks. Platinumdna interactions and subsequent cellular processes. Nfe2related factor 2 nrf2, a key transcription regulator for antioxidant and detoxification enzymes, is abundantly expressed in cancer cells. Direct imaging of the uptake of platinum anticancer agents using xray stimulated fluorescence. Unlike cisplatin and oxaliplatin, which form dna crosslinks, pyriplatin binds dna in a monofunctional manner. Platinumbased anticancer drugs, represented by cisplatin, play important roles in present cancer chemotherapy. We report the design, evaluation, and photoactivation mechanism of phorbiplatin, a platinum iv antitumor prodrug that can be controllably activated by red light. The present and the future of platinumbased anticancer drugs. Therefore, the synthesis of other platinum anticancer drugs e.
Western michigan university, 2015 cancer is considered the second leading cause of death after heart attack. Cisplatin is a chemotherapy medication used to treat a number of cancers. Antimetabolites can increase or decrease the number of platinumdna adducts. Cellular responses to platinumbased anticancer drugs. Cellular entry of ptbased drugs is thought to occur by both passive diffusion and carriermediated active transport. Nfb is a key to this understanding due to its importance in determining the final cell response to platinum drugs. The science world still requires improvement on these complexes because of multidrug and antineoplastic resistances. Platinumdna adducts activate several cellular processes that are responsible for the cytotoxicity of the drug. Impaired actin filaments decrease cisplatin sensitivity. Nrf2 enhances cell proliferation and resistance to anticancer. Platinumdna adducts, which are formed following uptake of the drug into the nucleus of cells, activate several cellular processes that mediate the cytotoxicity of these platinum drugs. Phorbiplatin maintains its integrity without irradiation, but under irradiation with red light, the prodrug is quickly and efficiently activated, releasing oxaliplatin and ppa.
Dnadamaging agents have a long history of use in cancer chemotherapy. We report the design, evaluation, and photoactivation mechanism of phorbiplatin, a platinumiv antitumor prodrug that can be controllably activated by red light. The anticancer activity of cisplatin and other platinum drugs is believed to. Cancer cell have lost their ability to differentiate that means to specialize. Understanding and improving platinum anticancer drugs ncbi.
This composition was selected due to the high antimicrobial effect of silver and for the anticancer properties of platinum. Dinuclear platinum complexes as potential anticancer drugs. Cellular pharmacology of palladinumiii hematoporphyrin. It plays a major role in the treatment of a variety of cancers. Pdf cytotoxicity of platinum anticancer drugs in mammalian. Dinuclear platinum anticancer complexes with fluorescent n,nbis aminoalkyl1,4diaminoanthraquinones. Journal of medicinal chemistry 2005, 48 16, 51915202. Request pdf wang d, lippard sjcellular processing of platinum anticancer drugs. Nuclear factorkappa b as a resistance factor to platinum. While details of its molecular mechanism of action are not completely known, carboplatin is believed. Cells were treated with various concentrations of ptacd or cispt, and viable cell number was determined by 34,5dimethylthiazol2yl2,5diphenol tetrazolium bromide.
Despite the clinical success that has been enjoyed by cisplatin, carboplatin, and oxaliplatin, treatment with these compounds inflicts a number of deleterious sideeffects. It is slightly soluble in water and soluble in dimethylprimanide and n,ndimethylformamide. However, cancer cells acquire resistance to cisplatin. Anticancer drug, any drug that is effective in the treatment of malignant, or cancerous, disease. Both drugs form platinumdna crosslinked adducts, and cisplatin causes oxidative dna damage including the 7,8dihydro8oxo2.
In addition, the use of many anticancer drugs is limited by doselimiting toxicities as well as the development of drug resistance. Chemistry and molecular biology of platinum anticancer drugs. After removal of the chloride, platinum forms covalent bonds to the n7 of purine bases. However, the therapeutic efficacy of platinum drugs is limited by serious. Understanding and improving platinum anticancer drugs. Platinum anticancer drugs, chemical biology of chemical biology. A proofofconcept study impactinnovation platinum ptbased drug is one of the most widely used and effective anticancer agents. It is used to treat various types of cancers, including sarcomas, some carcinomas e. Recent developments of platinumbased anticancer drugs.
In order to deliver the platinum drugs directly into the cells, 2deoxyglucose 2dg conjugated platinum ii conjugated platinum ii complex for glucose transporter1 also known as gluti1 was designed to transport the drug to the cancer cells. Pdf understanding and improving platinum anticancer drugs. Mechanistic work, including a crystal structure analysis of platinummodified dna in the active site of rna polymerase ii, is discussed herein. Thus, the platinum atom binds covalently to the n 7 position of purines cf guanine to form 1,2 or 1,3 strand crosslinks and interstrand crosslinks. Cellular pharmacology of palladinumiii hematoporphyrin ix. Application of fluorescence microscopy for investigation of. The platinum ii complexes whose structure follows these rules represent the socalled classical platinum chemotherapeutics. The chemotherapy drugs cisplatin, carboplatin, and oxaliplatin are commonly used for the treatment of lung, colorectal, ovarian, breast, headneck, bladder and testicular cancers fig. Direct imaging of the uptake of platinum anticancer agents. This new class of chemotherapeutics was discovered during the course of investigation of the electric field. A new platinumii compound anticancer drug candidate with. Anticancer therapy with cisplatin and oxaliplatin is limited by toxicity and onset of tumor resistance. This thesis deals with various aspects of intracellular behavior of antitumoractive dinuclear platinum complexes, i.
Response to cabozantinib in renal cell carcinoma with cardiac metastases. Nanotechnology, biology and medicine on deepdyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips. Cellular entry represents the first step in the mechanism of action of platinum anticancer agents. In order to increase the benefit of current platinumbased drugs and to direct effort to obtain improved agents, it is of great importance to understand the molecular basis of acquired and intrinsic resistance. 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. The clinical use of a photosensitizer in the presence of light and. Cisplatin, carboplatin and oxaliplatin are platinum based drugs that are widely used in cancer chemotherapy. Metal complexes in cancer therapy an update from drug. Pt drugs are routinely used in combination with other drugs in the clinic, and these combinations can influence the platinumdna adducts. Pdf understanding and improving platinum anticancer. To assess oxidative dna damage as a mechanism of cisplatin and oxaliplatin cytotoxicity, 8oxodgdirected base excision repair.
Cisplatin is one of the most important anticancer drug for chemotherapy. Pyriplatin, cis diamminepyridinechloroplatinumii, a platinum based antitumor drug candidate, is a cationic compound with anticancer properties in mice and is a substrate for organic cation transporters that facilitate oxaliplatin uptake. Cisplatin was approved for the treatment of both ovarian and testicular cancer in 1978 and is also administered for many other types of solid tumors subsequently, carboplatin was approved in march, 1989 for. Platinum and goldbased drugs on cancer chen journal. Mechanisms of cisplatininduced apoptosis and of cisplatin sensiti vity. Usually, these have described the structureactivity relationships which have been established for platinum complexes.
Recent developments of platinumbased anticancer drugs detection and analysis in biological samples volume. Understanding how the platinum anticancer drug carboplatin. The cellular processing of platinum drugs involves a large number of. Although three or five platinumbased drugs have been approved for clinical use worldwide or in japan, many active researches are still ongoing to seek next generation platinumbased drugs with less side effect and higher efficacy. In order to increase the benefit of current platinum based drugs and to direct effort to obtain improved agents, it is of great importance to understand the molecular basis of acquired and intrinsic resistance. The aquatedactivated platinum complexes can react with nucleophilic centers on purine bases of dna, particularly the n7 positions of guanosine and adenosine residues. Platinum drugs for treating cancer metals in medicine.
Kalayda gv, jansen baj, wielaard p, tanke hj, reedijk j. Jul 01, 2008 cellular entry represents the first step in the mechanism of action of platinum anticancer agents. Among those affecting patient quality of life are nephrotoxicity, fatigue, emesis, alopecia, ototoxicity, peripheral neuropathy, and myelosupression 24, 25. Few, if any, have dealt with polymeric species containing platinum, which is. Some platinum coordination complexes are active anticancer drugs in animals and man. Center for research and development of fine chemicals, state key laboratory breeding base of green pesticide and agricultural bioengineering ministry of education, guizhou university, guiyang 550025, p. Platinum neurotoxicity pharmacogenetics pubmed central pmc. Platinum and goldbased drugs on cancer chen journal of. There are several major classes of anticancer drugs. Polymeric platinumcontaining anticancer drugs johnson. Some of the platinum based antitumor drugs like cisplatin, carboplatin and oxaliplatin, have several disadvantages including side effects, cisplatinresistant tumors, limited solubility in aqueous media, and so on. Ncf119875, cisplatinum, also called cisdiamminedichloroplatinumii, is a metallic platinum coordination compound with a square planar geometry.
The plasticity and instability of the cancer genome is impressive and is characterized by gene amplifications and deletions, rearrangements, and many silent and active mutations. Pyriplatin, cis diamminepyridinechloroplatinumii, a platinumbased antitumor drug candidate, is a cationic compound with anticancer properties in mice and is a substrate for organic cation transporters that facilitate oxaliplatin uptake. Application of fluorescence microscopy for investigation of cellular distribution of dinuclear platinum anticancer drugs. A major part of this thesis is focused on the investigation of cellular processing of dinuclear platinum anticancer drugs using fluorescence microscopy.
Pharmacology notes ppt pdf anticancer drugs what is. The full extent of their cellular mechanisms, which is essential to balance efficacy and toxicity, is often unclear. Carboplatin, cisdiamminecyclobutane1,1dicarboxylato platinum ii, fig. Several cellular pathways are activated in response to this interaction, which include recognition by high.
Platinumdna interactions and subsequent cellular processes controlling sensitivity to anticancer platinum complexes. Copper transporters, including ctr1, facilitate cellular uptake of cisplatin and oxaliplatin, but their importance in mediating. Oct 01, 2016 read graphene quantum dots enhance anticancer activity of cisplatin via increasing its cellular and nuclear uptake, nanomedicine. Different treatments have been applied to kill cancer cells such as chemotherapy, which is the use of chemicals or drugs in order to treat cancer cells. Many clinical trials using combinations of platinum drugs and parp1 inhibitors parpi have been carried out, with the hope that such combinations will lead to enhanced therapeutic outcomes against tumors. It is a white or deep yellow to yelloworange crystalline powder at room temperature. Cisplatin, cisdiamminedichloroplatinumii, is widely used and among the most effective cancer chemotherapy drugs used to treat various types of cancers including sarcomas, small cell lung cancer, ovarian cancer, lymphomas, and germ cell tumors.
Platinum complexes which are most studied metal complexes due to their importance as adjuvant therapy of cancers aiming to induce tumorcelldeath. Mechanistic work, including a crystal structure analysis of platinum modified dna in the active site of rna polymerase ii, is discussed herein. Developments in platinumgroup metals as dual antibacterial. Cisplatin, carboplatin and oxaliplatin are platinumbased drugs that are widely used in cancer chemotherapy. Characterization of the effects of cisplatin and carboplatin on cell. Base excision repair of reactive oxygen speciesinitiated 7,8. Pdf approximately half of all patients who receive anticancer chemotherapy are treated. We used three human lung cancer cell lines with different degrees of nrf2 activation. Each phone is tested to make sure it is fully working, and that the serial number is clear before we ship it to you. Platinumgroup pg complexes have been used as antibacterial and anticancer agents since the discovery of cisplatin. To improve the selectivity and efficacy and to mitigate the damaging side effects of cisplatin, photosensitized derivatives, which can only be activated upon light irradiation in cancerous cells, have been introduced as anticancer drugs. Although targeted therapeutics have had effect in some diseases, there remains a large role for new cytotoxic agents that have the potential to be broadly active across multiple cancers. A platinumbased anticancer drug is any agent that contains one or more platinum atoms in the oxidation state of ii or iv, contains mono or multidentate nonlabile ammine carrier ligands and labile chlorido or bidentate carboxylate ligands, and which acts as a prodrug. A platinum based anticancer drug is any agent that contains one or more platinum atoms in the oxidation state of ii or iv, contains mono or multidentate nonlabile ammine carrier ligands and labile chlorido or bidentate carboxylate ligands, and which acts as a prodrug.
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