The importance and limitations of the alkylating agents as chemothenapeutic drugs and as tools for examining the basic mechanisms involved in carcinogenesis and muta. 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, fojo et al. Due various side effects as well as drug resistance, other anticancer. Inside the cell, the chloride atoms of cisplatin may be displaced and the compound may be inactivated directly by. The current accepted paradigm about cisplatin mechanism of action is that. Your dosage will be based on your medical condition, weight, and response to.
Mechanisms of action of cancer chemotherapeutic agents. Pdf approach to understanding the mechanisms of action. Cisplatin is a cancer medication that interferes with the growth of cancer cells and slows their growth and spread in the body. Understanding mechanisms underlying specific chemotherapeutic responses in subtypes of cancer may improve identification of treatment strategies most likely to benefit particular patients. The first tab in this file canonical coverage shows each species in the cisplatin canonical mechanism of action, the gene name or corresponding protein, and the method of. The biochemistry of cisplatin and current views of its mode of action comprise part 3, while part 4 focuses on the chemistry relevant to interactions of platinumii species with biomolecules. Cisplatin terry clayton biological inorganic chemistry april 1, 2007 slideshare uses cookies to improve functionality and performance, and to provide you with relevant advertising.
Enhancement of antitumor activity and circumvention of drug resistance. Cisplatin dosing, indications, interactions, adverse. The other two ligands in carboplatin are present in a ring structure rather than as two chloride atoms in cisplatin. Ruihua wang 1, kc moyung 2, yj zhao 2, karen poon 2.
A mechanism for the temporal potentiation of genipin to. The general mechanism of action of cisplatin in tumor cells is that it forms crosslinks with the purine bases of the dna, causing dna damage. Definitive information about the mechanism of action of cisplatin includes four key steps. Cisplatin and other platinumii analogs are widely used in clinical practice as anticancer drugs for a wide range of tumors. It was approved by the fda in the 1980s and since then it has been. Tumors with codeletion of the methylthioadenosine phosphorylase gene, as a consequence of p16 deletions, may be particularly sensitive to pemetrexed. Biochemical mechanisms of cisplatin cytotoxicity bentham. Cisplatin and doxorubicin induce distinct mechanisms of ovarian follicle loss. It is given by injection into a vein common side effects include bone marrow suppression, hearing.
Cisplatin is biochemically similar to bifunctional alkylating agents as it inhibits dna synthesis. Inside the cell, the generally accepted major cytotoxic mechanism of action of cisplatin. This commonality of action often yields overlapping cellular response mechanisms and can thus detract from drug efficacy. Anderson3, norah spears1 1centre for integrative physiology, university of edinburgh, edinburgh, scotland, united kingdom, 2edinburgh cancer research centre. In this way, cisplatin can be thought of as a monkey wrench in the dna repair system. More important, vitamin supplementation has not been shown to adverse ly affect efficacy in some tumor types. A specific section is devoted to discuss the pathogenesis of cisplatin. Biochemical modulation of cisplatin mechanisms of action.
For this reason, emphasis will be placed on cisplatin, which has been studied in greater detail and, therefore, allows us to. Department of gastroenterology, shenzhen hospital of southern medical. Pdf cisplatin is a chemotherapeutic drug that has been used in the treatment of. Frontiers mechanisms of cisplatininduced ototoxicity. Cisplatin for injection is a highly emetogenic antineoplastic agent. Inside cells, amifostine detoxifies reactive metabolites of platinum and alkylating agents, as well as scavenges free radicals.
Ever since the initial discovery of the anticancer activity of cisplatin, major efforts have been devoted to elucidate the biochemical mechanisms of antitumor activity of cisplatin in order to be able to rationally design novel platinum based drugs with superior pharmacological profiles. Although cisplatin uptake is not saturable or inhibited by structural analogs, a. 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. Anderson cancer center, 1515 holcombe boulevard, houston, tx 770304009, usa cisplatin is one of the most potent antitumor agents. Cisplatin is a highly effective antineoplastic drug with an extremely current mechanism of action. Cisplatin side effects, dosage, interactions drugs. Resistance mechanisms that limit the extent of dna damage include reduced drug uptake, increased drug inactivation, and increased dna adduct repair. Molecular mechanisms of action and drug resistance development in cancer chemotherapy. If you continue browsing the site, you agree to the use of cookies on this website. If cisplatindna adducts are not efficiently processed by cell machinery. The mechanism of action of cisplatin has been associated with ability to. Pharmacology and mechanism of action of pemetrexed.
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 comes as a liquid that is injected into a vein over six to eight hours in a hospital or medical facility. This thesis will describe the work in the area of molecular biology and biochemistry to improve our understanding of the functions of hmgb proteins in the mechanism of action of cisplatin. It has been used for treatment of numerous human cancers including bladder, head and neck, lung, ovarian, and testicular cancers. Despite its undeniable therapeutic value, we still do not fully understand the mechanisms of action responsible. Origins of these pharmacologicbased mechanisms, however, are at the. Cisplatinresistant triplenegative breast cancer subtypes. Platinol cisplatin for injection, usp should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. This is a pdf file of an unedited manuscript that has been accepted for publication. 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, the mechanism by which these adducts kill cells is less well understood. It is given by injection into a vein common side effects include bone marrow suppression, hearing problems, kidney problems. 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. Other possible effects include accelerated dna repair, induction of cellular hypoxia, inhibition of apoptosis, alteration of gene expression and modification of enzyme activity.
Most cisplatin enters the body through active transport, but some molecules are. Cisplatin is a chemotherapy medication used to treat a number of cancers. Appropriate management of therapy and complications is possible only when adequate. Imatinib provides selective protection only against cisplatin stephanie morgan1, federica lopes1, charlie gourley2, richard a. The examples compiled in part 5 elucidate the impact of cisplatin on specific fields within inorganic chemistry, from the platinum blues to platinumiii. New insights into the mechanism of action of antioxidants. In comparison, aki induced by the cancer chemotherapeutic and prominent nephrotoxicant cisplatin.
In chapter 1, the molecular biology of cisplatin and hmgb proteins is described based on previously reported in vivo and in vitro experiments. Like cisplatin, it contains a platinum atom surrounded in a plane by two ammonia groups and two other ligands in the cis position. Cisplatin, cisplatinum, or cisdiamminedichloroplatinum ii, is a wellknown chemotherapeutic drug. The primary mechanism by which they exert their action is through the formation of adducts with genomic dna. 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. Coverage of the cisplatin canonical mechanism of action and ecn seed species related to figure 4.
The biological target of cisplatin and effects of platination on structure after the discovery of the anticancer properties of cisplatin, work began to investigate its 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 replace one of the chloride ions. The mechanisms responsible for cisplatin resistance are several, and contribute to the multifactorial nature of the problem. Molecular mechanisms of cisplatin resistance oncogene. To overcome resistance, cisplatin is commonly used in combination with some other drugs in. 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. Frontiers cisplatinmembrane interactions and their. The mechanisms mediating renal cell death induced by nephrotoxicants and renal pathologies are strikingly similar. Patients were randomized to receive either gemcitabine mgm 2 on days 1, 8, and 15 of each 28day cycle with cisplatin 100 mgm 2 on day 1 after gemcitabine administration n260 or cisplatin 100 mgm 2 on day 1 of each 28day cycle n262. Cisplatin or cis diamminedichloroplatinum ddp is an inorganic compound that is widely used for the treatment of a variety of tumors. Cancer presents the second most common cause of death in. 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.
With the hmg protein bound to the dna, the modified strand is. Preclinical anticancer activity and multiple mechanisms. However, multiple cellular targets by platinumii complexes have been described. Cisplatin, platinumbased drugs, mechanisms of action. Weiner rituximab is a mainstay in the therapy for a broad variety of bcell malignancies. Cisplatin biochemical mechanism of action current medicinal chemistry, 2003, vol. Structure, recognition, and processing of cisplatin dna. The major efficacy outcome measure was overall survival. One of the first issues that needed to be settled was its biological target, for there are many cellular components that can react with cisplatin. It has been shown to selectively inhibit tbk1 and ikk, producing reversible weight loss and improved insulin sensitivity, it is through this mechanism that it has produced substantial results in terms of reducing hba1c. Pdf biochemical modulation of cisplatin mechanisms of. For example, triplenegative breast cancer tnbc patients have variable response to the chemotherapeutic agent cisplatin. Division of cancer prevention, national cancer institute.
A mechanism for the temporal potentiation of genipin to the cytotoxicity of cisplatin in colon cancer cells. In this chapter, the mechanism of action of some established dna interactive agents will be discussed, but for many the detailed information is scant and very little is known regarding events following dna damage. 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. Many clinically available anticancer compounds are designed to target dna. The format and content of the drug monographs, regimen. There are three key players involved in cisplatins mechanism. 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 with normal transcription, and or dna replication mechanisms. Forhycamtin for injection in combination with cisplatin, reduce the dose to 0. The overwhelming dna damage caused by formation of dna adducts interferes with the dna replication and repair mechanisms, which subsequently induces apoptosis dasari and tchounwou, 2014. It is effective against various types of cancers, including.