Anti-cancer drugs

Cisplatin: The first metal based anticancer drug.

The demonstration in the 1960's that cis-diamminedichloroplatinum(II), or cisplatin, inhibits cellular division of Escherichia coli1 led to the subsequent discovery that this simple coordination compound is also an effective antitumor agent in mouse models.2 Subsequent studies validated cisplatin as an effective anticancer agent in humans as well,3–7 and FDA approval of cisplatin for the treatment of metastatic ovarian and testicular cancers was granted in 1978.8 Its introduction as a chemotherapeutic agent significantly improved the survival outlook for many cancer patients; the cure rate for testicular cancer before the approval of cisplatin was less than 10%, significantly lower than the 90% cure rate attained with modern platinum chemotherapy.9,10

Cisplatin kills cancer cells primarily by cross-linking DNA and inhibiting transcription.11 The chemical origin of this process begins when cisplatin enters the cell and undergoes aquation involving loss of one or both chloride ligands. The resulting platinum(II) aqua complexes are potent electrophiles that readily react with a number of biological ligands with loss of the bound water molecules. The purine bases of nucleic acids are strongly nucleophilic at the N7 position. Thus, cisplatin binds readily to DNA, forming primarily bifunctional adducts with loss of both chloride ligands. The major cisplatin-DNA adduct is the intrastrand 1,2-d(GpG) cross-link, which accounts for 60–65% of the bound platinum.12 The resulting Pt-DNA adducts, which distort and bend the DNA structure,13–15 impede transcription.16 The downstream effects of transcription inhibition ultimately lead to cell death.

Despite its great curative success in testicular cancer, cisplatin is not universally effective in other cancer types and induces a number of toxic side effects.17–19 Additionally, certain cancers are resistant to cisplatin therapy. This resistance is either intrinsic or developed during prolonged treatment.20,21 To circumvent these problems, new platinum complexes have been pursued and investigated for their antitumor properties. Although well over a thousand complexes have been prepared and tested thus far,22 only two other platinum drugs are approved for clinical use worldwide, and three additional compounds are approved for regional use in Asia.23 These complexes, displayed in Chart 1, operate with a mechanism of action similar to that of cisplatin, which involves DNA binding and transcription inhibition.






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Chart 1


Chemical structures of the clinically used platinum-based anticancer drugs. The top three complexes, cisplatin, carboplatin, and oxaliplatin, are approved for use worldwide. The bottom three complexes, nedaplatin, lobaplatin, and heptaplatin, are approved for use in Japan, China, and Korea, respectively.

/pdf/synthetic-methods-for-the-preparation-of-platinum-anticancer-4et0np31b8.pdf

Synthetic Methods for the Preparation of Platinum Anticancer Complexes

What do we know about the reduction of Pt(IV) pro-drugs?

Two major issues which hamper the use of the anticancer drug cisplatin are the development of cancer cell resistance and its nephrotoxicity. One possible mechanism by which resistance is reported to develop is a reduction in drug uptake across the cell membrane. While the passive uptake of cisplatin has long been cited as an important contribution, far greater attention has been given to active modes of uptake, particularly in recent research. Using unilamellar lipid vesicles together with the stopped-flow kinetic method we show here that the permeability coefficient of cisplatin increases significantly with the chloride concentration of the medium. This supports the hypothesis that cisplatin can enter cells via passive permeation through the lipid phase of the membrane, but becomes trapped within the cytoplasm because dissociation of chloride ligands yields a membrane-impermeant positively-charged aqua derivative. This is important evidence for a major role of passive membrane diffusion in the uptake of cisplatin, and suggests that reduced cell uptake is unlikely to be a significant mechanism leading to the development of drug resistance. Studies of rubidium ion uptake into the cytoplasm of Xenopus oocytes via the Na+,K+-ATPase show significant inhibition of this ion pump when cisplatin is present in the cytoplasm. Because Na+,K+-ATPase activity is essential to the survival of all animal cells, e.g. via maintenance of cell volume, and the Na+,K+-ATPase is expressed at particularly high levels within the membranes of kidney tubules where it plays a crucial role in nutrient reabsorption, these results suggest that cisplatin-induced inhibition of the Na+,K+-ATPase is a likely contributing cause for the nephrotoxicity of cisplatin.

/pdf/mechanisms-of-cell-uptake-and-toxicity-of-the-anticancer-574llfwtod.pdf

Mechanisms of cell uptake and toxicity of the anticancer drug cisplatin.

The aquation and hydrolysis of a series of platinum(IV) complexes of the general form cis, trans, cis-[PtCl2(X)2(15NH3)2] (X = Cl−, O2CCH3−, OH−) have been followed by [1H,15N] Heteronuclear Single Quantum Coherence NMR spectroscopy. Negligible aquation (<5%) is observed for the complexes where X = O2CCH3− or OH− over 3−4 weeks. Aquation of cis-[PtCl4(15NH3)2] (1) is observed, and the rate of aquation increases with increasing pH and upon the addition of 0.01 mol equiv of the platinum(II) complex cis-[PtCl2(15NH3)2] (cisplatin). The first aquated species formed from cis-[PtCl4(NH3)2] has one of the axial chloro groups (relative to the equatorial NH3 ligands) replaced by an aqua/hydroxo ligand. The second observed substitution occurs in an equatorial position. Peaks that are consistent with five of the eight possible aquation species were observed in the NMR spectra.

[1H, 15N] Heteronuclear Single Quantum Coherence NMR Study of the Mechanism of Aquation of Platinum(IV) Ammine Complexes

There is much recent evidence showing that mitochondria play a critical role in the regulation of apoptosis (programmed cell death), making them an attractive target for the design of new anticancer drugs. Several different classes of gold-based compounds have attracted interest as potential antitumour agents and there is evidence that many act by mechanisms involving mitochondrial cell death pathways. 1 Two distinct classes of Au(I) phosphine complexes display antitumour properties, these having either linear two-coordinate, or tetrahedral four-coordinate geometries. Both classes appear to target mitochondria, but different mechanisms are likely to be involved, related to their differing propensity to undergo ligand exchange reactions with biological ligands. The anti-arthritic

http://rd.springer.com/content/pdf/10.1007%2Fs00775-007-0255-5.pdf

Trevor W. Hambley

Papers

[1H, 15N] Heteronuclear Single Quantum Coherence NMR Study of the Mechanism of Aquation of Platinum(IV) Ammine Complexes

1. METALS IN MEDICINE KEYNOTE LECTURES KL01 The mitochondrial cell death pathway as a target for gold and other metal-based antitumour compounds