Cisplatin mechanisms of action

Several models have been proposed to explain what specific role HMG-domain proteins could play in the cisplatin mechanism of action. When the ability of this family to recognize cisplatin-modified DNA was first detected, it was suggested that HMG-domain proteins might be factors that communicate the presence of the genetic damage to the repair pathways [117], but no evidence to date supports such a hypothesis. 

Fig. 5. Models for HMG involvement in the cisplatin mechanism of action. A) When a cell is exposed to a lethal dose of cisplatin, 104—105 DNA adducts are formed. If HMG-domain proteins bind with similar affinity to these lesions and to their natural binding sites, the proteins could be titrated away from their transcriptional regulatory function. B) The HMG-domain proteins could block access of the excision repair complex and...

Although the platinum-amino-acid complexes do not show much promise as cytotoxic agents, these results demonstrated the utility of in vitro screening methods to survey the DNA-binding properties of platinum compounds in a combinatorial manner. Assuming that HMG-domain proteins are involved in the cisplatin mechanism of action, then screening based on the Pt-... 

The mechanism of action of this unrelated group of drag is not entirely clear. Examples of miscellaneous antineoplastics include cisplatin (Platinol) and hydroxyurea (Hydrea). 

While carboplatin has the same mechanism of action as cisplatin, it has a much less toxic side-effect profile than cisplatin. The pharmacokinetics of carboplatin are best described by a two-compartment model, with an a half-life of 90 minutes and a terminal half-life of 180 minutes. Carboplatin is eliminated almost entirely by the kidney by glomerular filtration and tubular secretion. Many chemotherapy regimens dose carboplatin based on an area under the curve (AUC), which is referred to... 

Eastman, A. The Mechanism of Action of Cisplatin From Adducts to Apoptosis. In Cisplatin Chemistry and Biochemistry of a Leading Anticancer Drug Lippert, B., Ed. Wiley-VCH Weinheim, 1999, pp, 111-134. 

Several biological assays pointed to an unusual mechanism of action for 7, which is clearly different from cisplatin, as expected from its remarkable cytotoxic activity. For example, different levels of p53 and caspase activity were observed. Unusual... 

Although the specific mechanisms of action of cisplatin and its derivatives against different tumors are beginning to unfold [48— 52], it is, for example, still under dispute in which form the drug reaches the cellular DNA and binds to its targets, i.e. as Pt[NH3]2[H20][Cl]+ or as Pt[NH3]2[H20] + [53-55],... 

Fig. 1. Some of the factors involved in the mechanism of action and resistance of cisplatin.

Novel mechanisms of interest include sensitizing hypoxic tumor cell lines to enhance radiotoxicity. Tirapazamine is a hypoxia-selective compound 1-2-fold greater in magnitude in comparison to mitomycin C or porfiromycin (84). Its mechanism of action results in a one-electron reduction inducing DNA double-strand breaks and cell death under hypoxic conditions. The free radical is oxidized back to the parent compound under aerobic conditions. When combined with the platinum compounds, the cytotoxic effects may be equivalent to that seen with five times the dose of cisplatin without the toxicities that would be encountered if actually administered (85). 

Carboplatin is a platinum complex in which platinum is incorporated into a more complex molecule. Its mechanism of action and spectrum of anti-tumor activity are similar to those of cisplatin. However carboplatin is better tolerated that cisplatin. 

Investigations on the working mechanism of cisplatin have been carried out during the last decade by a variety of research groups, involving chemists, biochemists, biologists and medical researchers17. Early studies already made it clear that reaction of platinum compounds with nucleic adds play an important role in the mechanism of action. The present review deals with the status of this field, with special attention to platinum-DNA interactions. 

A variety of other compounds have mechanisms of action that involve alkylation. These include procarbazine, dacarbazine, altretamine (hexamethylmelamine), cisplatin, and carboplatin. Dosages and major toxicities are listed in Table 55-2. 

Oxaliplatin is a third generation diaminocyclohexane platinum analog. Its mechanism of action is identical to that of cisplatin and carboplatin. However, it is not cross-resistant to cancer cells that are resistant to cisplatin or carboplatin on the basis of mismatch repair defects. This agent was recently approved for use as second-line therapy in metastatic colorectal cancer following treatment with the combination of fluorouracil-leucovorin and irinotecan, and it is now widely used as first-line therapy of this disease as well. Neurotoxicity is dose-limiting and characterized by a peripheral sensory neuropathy, often triggered or worsened upon exposure to cold. While this neurotoxicity is cumulative, it tends to be reversible—in contrast to cisplatin-induced neurotoxicity. 

Gold(III) organometallics are isoelectronic with cisplatin-like Ptn complexes. For example, complex 10 hydrolyses in water [123] and has shown activity in human tumour xenograft models [124]. However, its mechanism of action is different from that of cisplatin [124,125]. The role of hydrolysis as an activation step for this class of compounds is not yet clear. 

The Mechanism of Action of Cisplatin From Adducts to Apoptosis... 

Reimplantation in vivo restored cisplatin resistance, demonstrating the importance of cellular context when examining drug sensitivity. For this reason, the mechanism of action of cisplatin should be examined in human tissue when possible. 

Experiments in this laboratory identified apoptosis as a consequence of the action of cisplatin and many other anticancer agents [50-52], Many authors have subsequently misquoted these results when suggesting that cisplatin kills by apoptosis, and that suppression of apoptosis is a mechanism of resistance. It should be evident by now that apoptosis is better defined as a consequence of the mechanism of action of cisplatin and a failure of the mechanisms of resistance. Apoptosis is certainly not an alternative to the formation of DNA cross-links, nor to the cell-cycle perturbations that result these are still essential events in the initiation phase of apoptosis. The mechanisms of resistance to cisplatin still include reduced drug accumulation, reduced DNA platination, and altered DNA repair. However, apoptosis provides a framework for understanding the complete pathway from initial insult to eventual death of a cell. It provides the realization that there are additional factors that influence cell survival and death. Expression of Bcl-2 family members or changes in signal transduction pathways impact... 

The mechanism of action of cisplatin is believed to involve activation via hydrolysis inside cells where the Cl- concentration is much lower (ca. 4 him) than outside cells (ca. 100 him) [10]. Ptn-OH2 bonds are more reac-... 

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