Cisplatin

1 Oe Cisplatin. Cisplatin [civ-diammincdichloroplatinum(II)] is a clinically used chemotherapeutic agent in the treatment of a variety of human cancers. The anticancer activity of cisplatin is believed to result from cytotoxicity induced by cisplatin DNA adducts. Not surprisingly, cisplatin itself is a mutagen and carcinogen. G - T and A — T transversions appear to be the main mutations induced by cisplatin. 

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A second family of carbohydrate-degrading enzymes, the lysozymes, produces synergistic antimetastatic activity when co-adrninistered with cisplatin [15663-27-1] to mice whose primary tumor had been surgically removed (51). 

Amongst these are bis(cyclopentadienyl) and bis(y3-diketonate) derivatives, some of which are undergoing clinical trials, in the hope that they will provide more extensive application than cisplatin (pp. 1163-4). 

Structure, recognition, and processing of cisplatin-DNA adducts 99CRV2467. 

Carboplatin (96) is significantly less toxic in the clinic than cisplatin. Most particularly, it is much less nephrotoxic. Use of a bidentate ligand also ensures formation of a ds complex. Its synthesis begins with cis-diammine platinum diiodide (94) which is reacted with silver sulfate to give cis-diaquodiam mine platinum sulfate (95). This is reacted with the barium salt of 1,1-cyclo-butanedicarboxylic acid to yield carboplatin [23],... 

The only prominent antitumor tetravalent platinum complex so far is iproplatin (102). In vitro it has been shown to cause interstrand DNA-breaking and cross linking. Free radical scavengers inhibit these effects. The complex is less neurotoxic and less nephrotoxic than cisplatin. Its synthesis begins with hydrogen peroxide oxidation of cis-dichlorobis(isopropvlamine) platinum (100) to the dimethylacetamide complex 101. The latter is heated in vacuum to liberate iproplatin [25]. 

Cisplatin, Pt (NH3)2Cl2, is a chemotherapeutic agent that disrupts die growth of DNA. If die current cost of Pt is 1118.0/troy ounce (1 troy oz = 31.10 g), how many grams of cisplatin can you make with three thousand dollars worth of platinum How many pounds ... 

The cis isomer ( cisplatin ) is an effective anticancer drug. This reflects the ability of the two Cl atoms to interact with the nitrogen atoms of DNA, a molecule responsible for cell reproduction. The trans isomer is ineffective in chemotherapy, presumably because the Q atoms are too far apart to react with a DNA molecule. 

When solutions containing the aqua complexes derived from cisplatin react with pyrimidines and other bases and are exposed to air, blue solutions (and solids) result [94], These are mixed-valence oligomers (n = 4). Some have anti-tumour activity but have not yet found clinical use. 

Figure 3.116 Platinum compounds studied for possible anti-tumour activity. I, ris-Dichlorodi-ammineplatinum(II) cisplatin, platinol NSC 119875 neoplatin platinex. II, a.s-Diammine(l,l-cyclobutanedicarboxylato)platinum(II) JM-8 paraplatin NSC 241240. Ill, Oxiplatin. IV, Tetraplatin. V, Amminediacetatodichloro(cyclohexylamine)platinum(IV). VI, cis-Dich oro-trans-dihydroxy-cis-bis(isopropylamine)platinum(IV) iproplatin JM-19 CHIP NSC 256927.

Dimeric complexes like [Cl(NH3)Pt H2N(CH2)4NH2 Pt(NH3)Cl]Cl2 are also being investigated as they bind to DNA in a different way to that involved in cisplatin binding and are active in cisplatin-resistant human tumour cells. They are more potent than cisplatin in lung cancer models in vivo and are likely to go on clinical trials in the near future [204],... 

The ability of cisplatin to be toxic to tumour cells is believed to relate to its binding to DNA, but since trans- [Pt (NH3) 2 Cl2 ] also binds to DNA, the reason for the inactivity of the trans-form is more complex. 

Figure 3.118 Possible modes of cisplatin binding to DNA strands. (Reproduced from J.J.R. Frausto da Silva and R.J.P. Williams, The Biological Chemistry of the Elements, 1994, p. 539, by permission of Oxford University Press.)...

Figure 3.119 cis-Pt(NH3)2[d(pGpG)], model compound for the binding of cisplatin to DNA. (Reprinted with permission from Science, 1985,230,430. Copyright (1985) American Association for the Advancement of Science.)... 

Binding of cisplatin to the neighbouring bases in the DNA disrupts the orderly stacking of the purine bases when it forms a 1,2-intrastrand crosslink, it bends the DNA helix by some 34° towards the major groove and unwinds the helix by 13°. These cross-links are believed to block DNA replication. 

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