Mechanism of Action of Carboplatin Oxaliplatin and Nedaplatin

Carboplatin forms a similar spectrum of DNA adducts as cisplatin with slightly different sequence preferences.22 Concentrations of carboplatin approximately two orders of magnitude higher are needed to obtain DNA platination levels equivalent to cisplatin. Conformational alterations induced in DNA by carbo-platin in cell-free media have been characterized23 and the changes of non-denaturational character similar to those observed for cisplatin at the same level of DNA platination have been found.

In order for the reaction of oxaliplatin with DNA to occur, the parent compound must become aquated. The hydrolysis of oxaliplatin to form reactive species, 1,2-DACH diaqua platinum(II) ([Pt(R,R-DACH)(H2O)2]2+), is a slower process than the hydrolysis of cisplatin. The sites in DNA of oxaliplatin adducts and their spectra are nearly identical to the situation when DNA is modified by cisplatin.24 On the other hand, oxaliplatin is inherently less able than cisplatin to form DNA adducts.25 Oxaliplatin adducts are repaired with kinetics similar as cisplatin adducts.26 However, oxaliplatin is more efficient than cisplatin per equal number of DNA adducts in inhibiting DNA chain elongation. Despite lower DNA reactivity, oxaliplatin exhibits similar or greater cytotoxicity in several human tumor cell lines (discussed earlier). Thus, oxaliplatin requires fewer DNA lesions than does cisplatin to achieve cell growth inhibition.25 The overall conformational alterations induced in DNA by the 1,2-GG intrastrand cross-link of cisplatin and oxaliplatin are similar, but also differ in several details.27 The bulky DACH ring of the oxaliplatin adduct fills much of the DNA major groove, making it narrower and less polar at the site of the cross-link. The subtle differences in overall conformation of 1,2-GG intrastrand cross-links of cisplatin and oxaliplatin have been suggested28 to influence further processing of the oxaliplatin cross-link in the cell.

Data on the molecular mechanism of anti-tumor effects of nedaplatin,29 which is cross-resistant with cisplatin as for carboplatin, indicate that this drug reacts with guanine residues, but it requires a reaction time about 20 times that required by cisplatin. Nedaplatin is a drug structurally similar to carboplatin so that it is reasonable to expect that nedaplatin forms the same types of DNA adducts as cisplatin and carboplatin. Interestingly, survival of the cultured cells of human ovarian cancer correlated with interstrand cross-linking efficiency of this platinum drug.29

Taken together, the adducts produced on DNA by direct analogues of cisplatin, such as carboplatin, oxaliplatin and nedaplatin, are similar to those produced by the parent drug, though different in their relative rates of formation. Hence, from a mechanistic DNA-binding point of view, it is not too surprising that the introduction of the three new platinum anti-tumor drugs in the clinic does not represent a fundamental breakthrough in the treatment of cancer with platinum agents. This conclusion prompted a formulation of the hypothesis that development of platinum compounds structurally dissimilar to cisplatin may lead to agents with a spectrum of clinical activity complementary to the parent drug.30 Moreover, as DNA is considered the major pharmacological target of platinum compounds, the latter hypothesis also implies that platinum agents which bind to DNA in a manner fundamentally different to that of cisplatin may have altered pharmacological properties. This concept has already led to the synthesis of several new unconventional platinum anti-tumor compounds that violate the original structure-activity relationships.

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  • rorimac
    What is the action of carboplatin?
    3 years ago

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