14 Cisplatin and other platinum containing compounds
14.2 Mechanism of Action of Cisplatin: Aquation
What is the mechanism of action of cisplatin in tumour cells? Following administration to the bloodstream (Figure 12.3), cisplatin maintains a stable neutral state, because of the high concentration of cloride ions (100 mM). Inside the cell, because of the lower chloride concentration of about 4 mM, one of the chloride ligands is replaced by water in a process termed aquation, retaining the cis-configuration. This aqua ligand in the resulting complex is itself easily replaced, allowing the platinum atomto bind to bases. The preferred base is guanine, as we have also heard for alkylating agents. Crosslinking can occur via displacement of the other chloride ligand, typically by another guanine.
DNA binding is the main biological event that triggers anticancer properties. Formation of cisplatin adducts significantly alters the structure of the target DNA. Cisplatin can crosslink DNA in several different ways, interfering with cell division. The damaged DNA elicits DNA repair mechanisms, which in turn activate apoptosis when repair proves impossible. 1,2-intrastrands d(GpG) and d(ApG) adducts (Figure 14.4) form nearly 90% of the adducts. 1,3-intrastrand d(gpXpG) adducts also occur but are readily excised by the nucleotide excision repair (NER) system (see chapter 21). A small percentage of interstrand cross-links and monofunctional adducts are also present. As we have already learned for alkylating agents, cisplatin also predominantly binds to the N-7 position of guanine bases, because this position is the most reactive one.
14.3 Side effects of cisplatin treatment
Cisplatin binds to a variety of cellular targets, many of them source of toxicity and undesired side-effects. Consequently, the mechanism of action of cisplatin is very complex. You do not have to understand this in detail, we only want you to show how complex the mechanism is.
A variety of proteins bind to DNA, following cisplatin damage ,initiating downstream signalling pathways (Figure 14.5). One class of proteins selectively recognise DNA-cisplatin lesions, includingDNA-damage recognition proteins. Another class of targets are proteins involved in DNA packaging or DNA dependent functions such as histones and DNA or RNA polymerases. The significance of these interactions to the anti-tumour mechanism is unknown, but they are likely to at least affect the general patient toxicity profile.
As an example, we want to look at one class of proteins, the so-called high mobility group (HMG) proteins. Platinum modification distorts the structure ofdouble-stranded DNA. HMG domain proteins preferentially bind to DNA with bent or distorted structures. Not astonishingly, they therefore interact with cisplatin-modified DNA. There is very good evidence for this, since the crystal structure of the cisplastin-DNA complex bound to a HMG domain has been determined (Figure 14.6). As a non-sequence-specific DNA binding protein, it regulates numerous nuclear functions including replication, transcription, recombination and general chromatin remodelling. Despite the wealth of information, however, it cannot be stated with certainty that this DNA-binding protein domain plays an essential role in conveying the anticancer activity of cisplatin.
14.4 Administration, Clinical Uses and Side Effects of Cisplatin
Cisplatin is administered intravenously as a short-term fusion.
Its clinical uses are small cell lung cancer, colorectal and ovarian cancer. Cisplatin in combination with bleomycin and vinblastine is particularly effective against testicular cancer with cure rates of up to 85%.
As you can imagine, cisplatin comes with a number of side-effects /toxicities. Acute toxicity include severe nausea and vomiting. More than 90% of all patients receiving cisplatin will suffer from this side effect.
Delayed toxicities include ototoxicity, which is hearing loss that may be severe or peripheral neurotoxicity, which is nerve damage. Another side effect can be bone marrow depression, which is the decrease in the production of red and white blood cells and platelets. Nephrotoxicity, which is kidney damage, is the dose-limiting toxicity (DLT). A decreased creatinine clearance, which can be monitored using a simple blood test, indicates poor renal function. This can be prevented and managed by adequate hydration.
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