Cisplatin treatment also caused the cells to be arrested at the DNA synthesis
DNA synthesis
DNA synthesis is the natural or artificial creation of deoxyribonucleic acid (DNA) molecules. The term DNA synthesis can refer to DNA replication - DNA biosynthesis (in vivo DNA amplification), polymerase chain reaction - enzymatic DNA synthesis (in vitro DNA amplification) or gene synthesis - physically creating artificial gene sequences.
Full Answer
How does cisplatin work in the body?
The way that cisplatin operates is by forming a platinum complex inside of a cell which binds to DNA. When DNA is cross-linked in this manner, the cell undergoes apoptosis, or systemic cell death. Damage to the DNA activates the cell's repair mechanisms.
How does cisplatin induce cell death in GCTs?
Cisplatin-induced cell death in GCTs is highly dependent on cell-cycle phase. All crucial events are restricted to the G2/M phase: cisplatin-induced DNA-damage is sensed, the apoptotic process is initiated and eventually executed in this phase of the cell cycle. The cells are most sensitive to cisplatin in this phase of the cell cycle.
Is cisplatin still used in chemotherapy?
New chemotherapy drugs have arrived on the scene over the past few decades, but cisplatin still finds wide use. Even when it is not the only or main drug given the the cancer patient, it can be a valuable part of a combination chemotherapy regimen.
What happens before and after a cisplatin infusion?
Before and/or after the cisplatin infusion, extra IV fluids are given and care is taken to ensure adequate hydration before both during and after cisplatin, to protect your kidney function. Cisplatin also has been used as an infusion into the abdominal cavity (contains the abdominal organs).
What is cisplatin used for?
It has been used for treatment of numerous human cancers including bladder , head and neck, lung, ovarian, and testicular cancers. It is effective against various types of cancers, including carcinomas, germ cell tumors, lymphomas, and sarcomas. Its mode of action has been linked to its ability to crosslink with the purine bases on the DNA; interfering with DNA repair mechanisms, causing DNA damage, and subsequently inducing apoptosis in cancer cells. However, because of drug resistance and numerous undesirable side effects such as severe kidney problems, allergic reactions, decrease immunity to infections, gastrointestinal disorders, hemorrhage, and hearing loss especially in younger patients, other platinum-containing anti-cancer drugs such as carboplatin, oxaliplatin and others, have also been used. Furthermore, combination therapies of cisplatin with other drugs have been highly considered to overcome drug-resistance and reduce toxicity. This comprehensive review highlights the physicochemical properties of cisplatin and related platinum-based drugs, and discusses its uses (either alone or in combination with other drugs) for the treatment of various human cancers. A special attention is given to its molecular mechanisms of action, and its undesirable side effects.
What are the structures of cisplatin, carboplatin, and oxaliplation?
Computational molecular structures of cisplatin, carboplatin and oxaliplation. These platinum compounds are composed of doubly charged platinum ion surrounded by four ligands; with the amine ligands on the left forming stronger interactions with the platinum ion, and the chloride ligands or carboxylate compounds on the right forming leaving groups allowing the platinum ion to form bonds with DNA bases (Goodsell, 2006).
How many analogues of cisplatin have been tested?
Since the early seminal work in the preclinical and clinical development of cisplatin, several thousand analogues have been synthesized and tested for properties that would enhance its therapeutic index. About 13 of these analogues have been evaluated in clinical trials, but only one (carboplatin) has provided definite advantage over cisplatin and achieved worldwide approval. Nine platinum analogues are currently in clinical trials around the world ormaplatin (tetraplatin), oxaliplatin, DWA2114R, enloplatin, lobaplatin, CI-973 (NK-121), 254-S, JM-216, and liposome-entrapped cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum (II) (LNDDP)] (Weiss and Christian, 1993). Figure 1presents the chemical structures of cisplatin and four of its analogs including carboplatin, oxaliplatin, ormaplatin and enloplatin.
How long does carboplatin stay in your system?
The diminished reactivity limits protein-carboplatin complexes, which are excreted. The lower excretion rate of carboplatin means that more is retained in the body, and hence its effects are longer lasting (a retention half-life of 30 hours for carboplatin, compared to 1.5-3.6 hours in the case of cisplatin).
How much does ciplatin weigh?
Cisplatin has a molecular weight of 301.1 gm/mol, a density of 3.74 g/cm3, a melting point of 270° C, a log Kowof -2.19 and a water solubility of 2.53 g/L at 25° C (HSDB 2009). Cisplatin was first synthesized by M. Peyrone in 1844 and its chemical structure was first elucidated by Alfred Werner in 1893.
What is the energy dependent process that leads to cell shrinkage?
Apoptosis is a controlled type of cell death which is energy-dependent leading to cell shrinkage, chromatin condensation, membrane budding, phosphatidylserine externalization, and activation of a family of cysteine proteases called caspases (Salvesen and Dixit, 1997;Cummings, Lasker et al., 2000).
What is CD133 ESA?
CD133, a surface glycoprotein linked to organ-specific stem cells, has been described as a marker of cancer-initiating cells in different tumor types. It has also been reported that a CD133+, epithelial-specific antigen-positive (CD133+ESA+) population is increased in primary non-small cell lung cancer (NSCLC) compared with normal lung tissue (Bertolini, Roz et al., 2009).
How is cisplatin cleared?
Cisplatin is cleared by the kidney by both glomerular filtration and tubular secretion [62]. Cisplatin concentrations within the kidney exceed those in blood suggesting an active accumulation of drug by renal parenchymal cells. Previous studies using kidney slices [63], cultured renal epithelial cells [64] and isolated perfused proximal tubule segments [65] have provided evidence for basolateral-to-apical transport of cisplatin. Studies in recent years have identified two different membrane transporters capable of transporting cisplatin into cells: Ctr1 and OCT2. Ctr1 is a copper transporter which was also shown to mediate cisplatin uptake into mammalian cells [66], including ovarian cancer cells [67]. Ctr1 is highly expressed in adult kidney and the protein localizes to the basolateral membrane of the proximal tubule [68]. Downregulation of Ctr1 expression in kidney cells in vitrodecreased both cisplatin uptake and cytotoxicity, suggesting that Ctr1 is an important cisplatin uptake mechanism in these cells [68]. The role of Ctr1 in cisplatin nephrotoxicity in vivohas not been examined. In addition, the organic cation transporter OCT2 (SLC22A2) transports cisplatin [69,70,71,72]. Cisplatin was shown to inhibit the uptake of other OCT2 substrates, consistent with the view that these substrates share a common transport pathway. Likewise, cimetidine, an OCT2 substrate, reduced cisplatin uptake and cytotoxicity in vitro[68,69,70] and cisplatin nephrotoxicity in vivo[61]. Two recent observations point to an important role for OCT2 in mediating renal cisplatin uptake and toxicity. First, knockout of the OCT2 gene significantly reduced urinary cisplatin excretion [60] and nephrotoxicity [60,61]. Second, a nonsynonymous single-nucleotide polymorphism (SNP) in the OCT2 gene (rs316019) was associated with reduced cisplatin-induced nephrotoxicity in patients [60,61]. The relevance of these findings to the possible prevention of cisplatin nephrotoxicity is discussed later.
How long does it take for cisplatin to restore renal function?
Recovery of renal function usually occurs over a period of 2–4 weeks, though more protracted courses, as well as lack of recovery are reported.
What is the role of caspases in apoptosis?
Caspases are a family of cell death proteases that play an essential role in the execution phase of apoptosis in cisplatin induced renal tubular epithelial cell death in vitroand in vivo[109,112,113,114].
What is the role of p21 in the cell cycle?
Control of the cell cycle is determined by the sequential activation and inhibition of the cyclin-dependent kinases (e.g., cdk2). p21, a cyclin dependent kinase inhibitor, is upregulated in kidney after cisplatin treatment and plays a protective role against toxicity . Thus, overexpression of p21 inhibits cisplatin-induced apoptosis in vitrowhile mice lacking the p21 gene are more sensitive to cisplatin nephrotoxicity in vivo[97,123,124]. The protective effects of p21 are due to its inhibition of cdk2, a cell cycle-associated kinase primarily active during late G1 through S phases [124,125]. Presumably, by inhibiting progression through the cell cycle, p21 allows time for cells to repair cisplatin-induced DNA damage.
How does platinum interact with DNA?
Platinum compounds are believed to mediate their cytotoxic effects through their interaction with DNA (Figure 1). In an aqueous environment, the chloride ligands of cisplatin are replaced by water molecules generating a positively charged electrophile. This electrophile reacts with nucleophilic sites on intracellular macromolecules to form DNA, RNA, and protein adducts [78]. Cisplatin binds to DNA leading to the formation of inter- and intrastrand cross-links, thereby arresting DNA synthesis and replication in rapidly proliferating cells [79]. The finding that cells deficient in DNA repair are more sensitive to cisplatin-induced cell death supports the concept that cisplatin mediates its anti-tumor effects through DNA damage. However, the primacy of nuclear DNA damage as the cause of cisplatin‑induced cell death has been challenged. In fact, only a small amount of cellular platinum (<1%) is bound to nuclear DNA and there is a poor correlation between the sensitivity of cells to cisplatin-induced cell death and the extent of DNA platination [80]. Moreover, Mandic et al.[81] used enucleated cells to demonstrate that cisplatin-induced apoptotic signaling occurs independently of nuclear DNA damage.
What is the process of degradation of damaged organelles, protein aggregates and other macromolecules in the cytoplasm?
Autophagy is a cellular process of degradation of damaged organelles, protein aggregates and other macromolecules in the cytoplasm. Treatment of renal epithelial cells with cisplatin causes the rapid expression of autophagic proteins and the formation of autophagosomes [119,120,121].
What is the protective effect of P21?
The protective effects of p21 are due to its inhibition of cdk2, a cell cycle-associated kinase primarily active during late G1 through S phases [124,125]. Presumably, by inhibiting progression through the cell cycle, p21 allows time for cells to repair cisplatin-induced DNA damage.
Why is cisplatin called the penicillin of cancer?
Cisplatin is called the “penicillin of cancer” because it is used so widely and it was the first big chemotherapy drug. Cisplatin also plays an interesting role in the history of chemistry. First synthesized in the 1800s, long before anyone thought of using it against cancer, cisplatin was a target compound chemists used to prove their moxie in inorganic synthesis. The shape and symbols of the molecule as represented in that discipline's iconography is aesthetically pleasing which is another reason people like to talk about cisplatin.
How many people have been given cisplatin?
The side effects can be serious – they vary from patient to patient of course – but hundreds of thousands of people have been given cisplatin and the medical establishment has learned how to deal with it.
What is the CAS number for Cisplatin?
The Chemical Abstract Registry (CAS) number is 15663-27-1.). The chemical formula is Pt (NH3)2Cl2. Molecular weight is 300.045. Cisplatin is soluble in water and delivered to the body in aqueous form.
What is the formula for cisplatin?
The chemical formula is Pt (NH3)2Cl2. Molecular weight is 300.045. Cisplatin is soluble in water and delivered to the body in aqueous form. Public Domain image from National Cancer Institute.
What happens when DNA is crosslinked?
When DNA is cross-linked in this manner, the cell undergoes apoptosis, or systemic cell death. Damage to the DNA activates the cell's repair mechanisms. Once the repair mechanisms are activated and the cells are found to not be salvageable, the death of those cells is triggered instead.
Is Cisplatin an old drug?
Cisplatin is frequently given as part of a combination chemotherapy regimen with other drugs. And even though it is an "old" drug as chemotherapy agents go (having been used for decades), it continues to find uses, especially as it is synergistic with other agents.
Is cisplatin still used?
By the late 1970s it was widely used and is still used today despite the many newer chemotherapy drugs developed over the past decades. Cancer Research UK has a great article about how cisplatin came to be recognized as a cancer drug. Cisplatin is off-patent.