Cisplatin cellular mechanisms

Damage repair DNA repair enzymes may become more ef cient in repairing defects caused by cisplatin. Inhibition of apoptosis due to activation of antiapoptotic cellular mechanisms. 

The major clinical problem encountered is the resistance against cisplatin. Some types of cancer are intrinsically insensitive to cisplatin treatment, whereas other cancers develop resistance during chemotherapy. This phenomenon limits the applicability of cisplatin to a relatively narrow range of tumors. The cisplatin-resistance mechanism seems to be multifactorial. Several main factors have been identified as potential modulators of cellular resistance, and are discussed below. 

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],... 

Andrews PA, Howell SB. Cellular pharmacology of cisplatin perspective on mechanisms of acquired resistance. Cancer Cells 1990 2 35 43. 

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. 

There are multiple pathways for p53 induction [161], but the specific mechanism for the activation of p53-mediated responses by cisplatin is still obscure. Details about the DNA-damage signal transduction pathway could be important for the mechanism of cisplatin resistance and must be provided by future research. In contrast, quite a lot is known about the downstream effects of p53. Several of these p53 activities have been implicated in the modulation of cellular sensitivity to cisplatin (Fig. 6). 

The mechanism by which cisplatin kills a cell represents a complex story. This review has identified numerous determinants of cellular response to cisplatin. DNA platination is an essential first step in the eventual demise of a cell, but the final outcome is also dependent upon the capacity for DNA repair, the ability to arrest cell cycle progression, the p53 status, the activity of intracellular protein kinase cascades, and the expression levels of pro-and anti-apoptotic members of the Bcl-2 family. It is likely that many other determinants remain to be identified. Many investigators are trying to predict the response of a tumor based on one or several of these parameters, but the above discussion would suggest it may be difficult if not impossible to predict sensitivity of a tumor to cisplatin without directly measuring it. 

The identification of the mechanisms of cisplatin translesion synthesis should allow the refinement of strategies aimed at minimizing the adverse effects of this cellular process. 

Figure 13 Mechanism of action and competing cellular targets of cisplatin. Solid arrows delineate the normal progression to formation of DNA lesions and dashed arrows represent nonproductive, dead-end reactions with other substances...

Kalayda GV, Jansen BAJ, Molenaar C, Wielaard P, Tanke HJ, Reedijk J. Dinuclear platinum complexes with N,N -bis (aminoalkyl)-l,4-diaminoanthraquinones as linking ligands. Part II. Cellular processing in A2780 cisplatin-resistant human ovarian carcinoma cells new insights into the mechanism of resistance. J. Biol. Inorg. Chem. 2004 9 414-422. 

Current opinion concerning the mechanism of delivery of liposomal therapeutics to tumors is that, once in the tumor, standard liposomes are localized in the extra-cellular fluid that surrounds the tumor cell but do not enter it i 8 ii Therefore, for delivery of the therapeutic agent, the drug must first be released into the extra-cellular fluid, from where it must then diffuse into the cell. There is the evidence that doxorubicin is released efficiently from Doxil liposomes, to be taken up by the cell in ovarian cancer and Kaposi s sarcoma. Concentrations of doxorubicin achieved in cells have been estimated as up to 13 times higher from Stealth liposomes than with a simple doxorubicin injection in patients undergoing treatment of Kaposi s sarcoma. hi contrast, evidence from the use of cisplatin seems less definitive. In studies comparing Stealth liposomal cisplatin (SPl-077) with standard cisplatin in... 

The toxicity is thought to be related to other heavy metal renal toxicity. In spite of the clinical importance and the relative frequency of this toxicity the mechanism of the toxicity remains unknown. A number of hypotheses have been put forward including altered mitochondrial function, activation of cisplatin, and inappropriate cellular binding, concentration of the heavy metal in the kidney, induction of apoptosis in... 

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