Mechanism of Cytotoxic Action

Little is known about the mechanisms by which some phosphines and metal phosphine complexes are able to kill cells. However, studies to date indicate that the phosphine itself is the cytotoxic agent. In the case of auranofin and other monophosphine Au(I) complexes, the role of the metal may be largely to protect the phosphine and deliver it to cellular targets. Auranofin is potently cytotoxic to cells in vitro, but its activity in vivo is limited This may be because Au(I) is very reactive towards biologically important ligands, particularly thiols so that it binds to proteins and is prevented firom reaching the critical targets. 

The high kinetic stability of bis-chelated Ag(I) diphosphines protects the Ag(I) ion from precipitation as AgCl in physiological fluids. For these complexes, the cytotoxic and 

Although there are some similarities in the chemistry of NH3 and PH3 there are many important differences. For example, NH3 is a much stronger base (pK, 9.21) than PH3 (pKa - 14). Comparison of the oxidation state diagrams for N and P (Fig. 1) demonstrates that NH4, in contrast to PH3, is not a strong reducing agent, and will not be readily oxidised in vivo. 

There may be many targets within cells where reactions with reactive phosphines could be destructive. In the next sections we will consider some possible reactions of phosphines in biological systems. It is interesting to note that PH3 itself is highly toxic and is widely used as a pesticide. 

PH3 is generated in situ by the action of moisture on Mg or A1 phosphide. In many countries, zinc phosphide is used as a rodentidde. It is usually mixed with some form of bait. Since Zn3P2 is hydrolysed only in addic conditions, it decomposes to PH3 only in the gut. The gas is toxic to insects, mites and all vertebrates including humans  

---

To study the mechanism of cytotoxic action of CNT we used a modified method of spin labels [20], which allows the quantitative determination of CNT influence on membrane integrity of human blood erythrocytes, and mitochondrial activity of hepatocytes in rat liver homogenate, without extraction of mitochondria from cells. 

Despite the many studies that have been conducted on the mechanism of cytotoxic action of Adr in tumor and heart, and those that have documented interactions between ICRF-187 and Adr, a role for iron in these processes has yet to be defined. In an effort to determine whether iron is required for the cytotoxic actions of Adr, several types of cells have been made iron deficient and tested for sensitivity to Adr. °°... 

Scheme 2. Postulated mechanisms of cytotoxic action initiated by saframycin A (5).

Crathorn, A.R., Robert, J.J., 1966. Mechanism of cytotoxic action of alkylating agents in mammalian cells and evidence for the removal of alkylated groups from deoxyribonuclei acid. Nature 211, 150-153. 

Kleszczynski, K. Skladanowski, A. C. Mechanism of cytotoxic action of perfluorinated acids. I. alteration in plasma membrane potential and intracellular pH level. Toxicol. Appl. Pharmacol. 2009,234, 300-305. 

Etoposide and teniposide are synthetic derivatives of the extract of the American mandragora plant (May Apple). The mechanism of their action has not been completely explained however, they act on the enzyme topoisomerase II, which disturbs the twisting of DNA. In addition, they inhibit DNA and RNA synthesis, as well as transport of nucleotides to cells. Cytotoxic action on normal cells is observed only in very high doses. These drugs exhibit significant activity in lymphomas, leukemia, Kaposi s sarcomas, and in testicular cancer. 

David, G. (2005) Covell Linking tumor cell cytotoxicity to mechanism of drug action An integrated analysis of gene expression, small-molecule screening and structural databases. Proteins Structure, Function, and Bioinformatics, 59 (3), 403-433. 

TGNs have a half-life of approximately one week with large variability (91,92). Several cytotoxic and immunosuppressant mechanisms of thiopurine action have been described (95, 96, 97, 98, 99,100). However, the major underlying mode of action in... 

The intermediate metabolite, me-TIMP, inhibits the purine de novo synthesis, thus interfering with replication and contributing to the cytotoxic effects of 6-MP (101,102,103). Thus, it becomes clear that thiopurines are likely to function at least as two-in-one drugs, and that different mechanisms of thiopurine action are associated to various extents with the clinically observed overall treatment effect of thiopurines. 

To clarify the mechanisms of antitumor actions of various chitosans, we examined the cytotoxic activity against YAC-1 (NK cell-sensitive target ceils) or sarcoma 180 cells by intestinal intraepithelial lymphocytes (lELs) or splenic lymphocytes treated various chitosans. Treatment of lELs with oligochitosan (10 to 1000 jlg/mL), chitosan-21 (10 to 1000 jXg/mL), or chitosan-46 (10 to 1000 jXg/mL) enhanced their c>i otoxic activity against YAC-1 cells compared with that of untreated lELs Fig. (12) . 

The antineoplastic activity of naphthomycin A (56) and its mode of action were reported. The antibiotic caused neither metaphase arrest nor prevented tubulin polymerization, and it was suggested that the mechanism of cytotoxicity of 56 was the inhibition of various SH enzymes, particularly those involved in nucleic acid biosynthesis [228,229]. 

The structural characteristics of individual PCB congeners influence their induction of various P450 activities. In mammals, PCB congeners have been characterized as 3-methylcholanthrene-type inducers, phenobarbital-type inducers, or mixed-type inducers of both. AHH and EROD activities (which are preferentially catalyzed by the P450IA gene subfamily) have been induced by planar PCBs in fish and mammals and by some mono- and di-ortho analogs of planar PCBs in mammals. The mechanism of toxic action of planar and mono-ortho planar PCBs is linked to an interaction with the 2,3,7,8-TCDD (or Ah) receptor protein. But this mechanism does not account for all observed PCB toxici-ties. Toxic responses uiuelated to Ah receptor effects have been reported of PCBs 4, 28, 31, 49, 52, 84, 95, 110, 136, and 153. For example, PCB 153 is less cytotoxic than PCB 169... 

An alternative mechanism of SAB action could involve its known effects on de novo purine biosynthesis (1, S) and/or nucleoside transport (5). The combined inhibitory effects of SAB and purine analogues on purine biosynthesis could result in sufficient depletion of intracellular nucleotide pools to result in enhanced cellular cytotoxicity. In addition, these effects would lead to an increased bioavailability of 5-phosphoribosyl-l-pyrophosphate (PRPP), the first enzymic product in the de novo pathway. Increased PRPP levels would enhance the activity of hypoxanthine phosphoribosyl transferase, leading to increased salvage of purine analogues. 

Discodermolide (36) is a cytotoxic polyketide isolated in low yield from the Caribbean sponge Discodermia dissoluta 44), The recent discovery that discodermolide shares the same microtubule-stabilising mechanism of antimitotic action as the clinically important anticancer drug, Taxol (paclitaxel), and retains activity against Taxol -resistant cancer cells has stimulated considerable interest (45,46). Due to the scarce supply of the natural material, the development of an efficient total synthesis (47-52) of (+)-discodermolide is needed to provide useful quantities for further testing, as well as enabling access to structurally simplified analogues. 

The above example of reduction-enhanced cytotoxicity is of particular relevance because of the role of copper as an essential trace element and its function in many intracellular redox processes. The arguments for an overall mechanism of radiobiological action invoking copper participation have, in fact, been presented [35] and will be summarized later. 

---