Platinum-containing anticancer drugs

Smith, C.J., Wilson, I.D., Abou-Shakra, F., Payne, R., Parry, T.C., Sinclair, P., Roberts, D. W. A comparison of the quantitative methods for the analysis of the platinum-containing anticancer drug cii-amminedichloro(2-methylpyridine)]-platinum(II) (ZD0473) by HPLC coupled to either a triple quadrupole mass spectrometer or an inductively coupled plasma mass spectrometer. Anal. Chem. 75, 1463-1469 (2003)... 

Cisplatin is a platinum-based compound (see structure below) that reacts with DNA causing it to crosslink, eventually leading to programmed cell death, also known as apoptosis. Cisplatin was the first in a class of platinum containing anticancer drugs. It has been used to fight several types of cancer and is particularly effective against testicular cancer. 

The many works related to platinum-containing anticancer drugs include a review of the binding of Cisplatin to DNA. Also of importance in this field are two communications concerning the known preference of Pt(II) to bond to N-7 of guanine and its derivatives. The affinity of platinum for particular sites is enhanced by the presence of an adjacent guanine. The active species of Cisplatin are ci5-[PtCl2(NH3)2] itself and the mono-aquo cation with which it equilibrates. 

Maleic copolymers were proved to form chelates with platinum-containing anticancer drugs (cis-diamminedichloroplatinum(II), trans-l,2-diaminocyclohexane platinum) through a monocarboxylato and a 0->Pt coordination linkage. These complexes self-assembled into nanoparticles with an increased in-vivo tumors inhibition due to their internalization into the cancer cells. The release of the platinum-containing drug was pH dependent [211,212]. 

Radical induced redox chemistry of platinum-containing anticancer drugs... 

Another subject which has featured regularly in this section has been the mode of action of platinum-containing anticancer drugs. Two more reviews relate to this subject, and several kinetic studies are listed in Section 5.2. 

The discovery of the anticancer activity of cisplatin was nothing less than monumental. To date, thousands of platinum-containing compounds have been investigated as potential chemotherapy drugs. Worldwide annual sales of platinum-based anticancer drugs are currently in excess of 2 billion. 

Many complexes and coordination compounds exist as isomers, compounds that contain the same numbers of the same atoms but in different arrangements. For example, the ions shown in (13a) and (13b) differ only in the positions of the Cl ligands, but they are distinct species, because they have different physical and chemical properties. Isomerism is of more than academic interest for example, anticancer drugs based on complexes of platinum are active only if they are the correct isomer. The complex needs to have a particular shape to interact with DNA molecules. 

The polymeric nature may inhibit premature drug deactivation. Thus, cisplatin (structure 19.20), the most widely used anticancer drug, is converted into numerous inactive, but more toxic, platinum-containing compounds before it arrives at the targeted cancer cells. Placement of the active platinum-containing moiety into a polymer (structure 19.21) decreases this tendency to hydrolyze into these unwanted cisplatin compounds because of the greater hydrophobic character of the polymeric drug. 

Cisplatin (dx-Diamminedichloroplatinum) is a divalent water-soluble platinum containing complex. It reacts directly with DNA, resulting in both intra-and inter-strand cross-links. It also causes DNA breaks and it inhibits DNA replication and RNA transcription. A mechanism for the occurrence of resistance appears to be an increased of the levels of DNA-excision repair enzymes. Cisplatin is used in combination therapies with other anticancer drugs in the treatment of testicular and ovarian cancers and it has also shown high activity against cancers of the bladder, head, neck and endometrium. It is administered intravenously by rapid injection or by continuous infusion. It is for more that 90% bound to... 

There is experimental evidence that several anticancer drugs can cause abnormalities of sperm chromosomes. Preliminary data have suggested that after platinum-containing chemotherapy for testicular cancer, penetration of oocytes can be severely impaired. Cytogenetic... 

Copper uptake across the gastrointestinal tract is poorly understood — most probably utihsing the divalent cation transporter DMTl. At the cellular level, Cu is imported across the plasma membrane of mammalian cells as Cu, by members of the CTR family. The CTR family of proteins have been found in yeast and plants, as we saw, but also in humans and other mammals. They contain several methionine-rich motifs at their N-terminus, and conserved cysteine and histidine residues at their C-terminus. Unusually, CTR proteins can mediate the uptake of platinum anticancer drugs into mammalian cells (see Chapter 22). 

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