Cytotoxic metals

The nature of the target to be attacked by any drug obviously depends on the specific application. Many cytotoxic metal complexes target DNA because of its importance in replication and cell viability. Coordination compounds offer many binding modes to polynucleotides, including outer-sphere noncovalent binding, metal coordination to nucleobase and phosphate backbone... 

Today, testing for antiproliferative activity is usually done in colorimetric cell culture assays, such as the MTT assay (MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide). As described in the introduction, the combination of cell-targeting peptides with cytotoxic metal complexes has the potential of providing more specific drug candidates with less side effects. However, this concept has so far only rarely been realized. 

Molybdocene dichloride (CP2M0CI2) is another cytotoxic metal complex that has been evalnated for its in vitro biological activity following Q[7] encapsnlation. Cp2MoCl2 Q[7] was fonnd to have improved activity when compared to free CP2M0CI2 with the 2008 cell line and the MCF-7 cell line. It is not known whether the improvement is related to solnbility or membrane permeability. ... 

Chelating agents may serve to effect an imbalance by depletion or activation of an essential metal ion in the target cell, rather than host cell. Cytotoxic metal ions or complexes may also be directed specifically toward the target cell, limiting their toxic effect to the host, and this is clearly of importance in design of antitumour agents. 

Mean arterial pressure and cardiac output, an expression of the amount of blood that the heart pumps each minute, are the key Indicators of the normal functioning of the cardiovascular system. Mean arterial pressure is strictly controlled, but by changing the cardiac output, a person can adapt, e.g., to increased oxygen requirement due to increased workload. Blood flow in vital organs may vary for many reasons, but is usually due to decreased cardiac output. However, there can be very dramatic changes in blood pressure, e.g., blood pressure plummets during an anaphylactic allergic reaction. Also cytotoxic chemicals, such as heavy metals, may decrease the blood pressure. 

Woody, R. D., Huget, E. F. and Horton, J.E. Apparent Cytotoxicity of Base Metal Casting Alloys , Journal of Dental Research, 56, 739-743 (1977)... 

In contrast to this view, but in analogy with the behavior of several antitumor metal complexes, some authors proposed that the DNA is the probable target for cytotoxic activity of organotin(IV) compounds. In this section we survey and compare the most important literature data published to date on this subject. 

Gielen, M. Willem, R. In Hadjiliadis, N. D. (Ed.), Cytotoxic, Mutagenic and Carcinogenic Potential of Heavy Metals Related to Human Environment, NATO ASI Series 2 Environment, Kluwer Academic, Dordrecht, 1997 Vol. 26, p. 445. 

The copper(II) complexes of 3-ethoxy-2-oxobutyraldehyde bis(thiosemicarbazone) and related compounds are active in vivo agents [151, 158, 159]. The metal complexes of 2-heterocyclic thiosemicarbazones were evaluated for their cytotoxicities [160, 161]. Further studies have revealed that these ligand s iron and copper complexes are effective inhibitors of DNA synthesis at much lower concentrations than the free thiosemicarbazones without apparent cytotoxicity [127]. Although the iron(III) complex of 2-isoformylquinoline thiosemicarbaz-one, 21, is considerably more active than free 21, the copper(II) complex is only moderately more active [127]. 

The cytotoxicity of LDL can also be inferred from the study by Blake et al. (1985). In this study of human cultured endothelial cells, stored sera from patients with necrotizing arteritis demonstrated an enhanced tendency to develop oxidized LDL, which correlated closely with endothelial cell cytotoxicity. This process appears to require the presence of both oxygen and transition metal ions such as iron in the presence of a reducing agent (Gebicki ef /., 1991). There is considerable evidence that transition metals are involved in cell-induced modifications of LDL including the inhibitory effects of EDTA and desfer-rioxamine (Hiramatsu et 1987). A role for Of in LDL modification by endothelial cells and fibroblasts comes from studies showing inhibition of LDL oxidation by SOD (Steinbrecher, 1988). 

The release of heavy metals into the environment presents a serious threat. Over recent decades, the annual worldwide release of heavy metals reached 22,000 T for cadmium, 939,000 T for copper, 783,000 T for lead, and 1,350,000 T for zinc.3 Because of their high solubility in the aquatic environments, heavy metals can be absorbed by living organisms and enter the food chain.6 Exposure to high levels of these metals has been linked to cytotoxic, mutagenic, and carcinogenic effects on... 

Dhir H, Sharma A, Talukler G. 1985. Alteration of cytotoxic effects of lead through interaction with other heavy metals. Nucleus 28 68-89. 

Deng WJ, Louie PKK et al (2006) Atmospheric levels and cytotoxicity of PAHs and heavy metals in TSP and PM2.5 at an electronic waste recycling site in southeast China. Atmos Environ 40(36) 6945-6955... 

Variation of the content of impurities in the different CNT preparations [21] offers additional challenges in the accurate and consistent assessment of CNT toxicity. As-produced CNTs generally contain high amounts of catalytic metal particles, such as iron and nickel, used as precursors in their synthesis. The cytotoxicity of high concentrations of these metals is well known [35, 36], mainly due to oxidative stress and induction of inflammatory processes generated by catalytic reactions at the metal particle surface [37]. Another very important contaminant is amorphous carbon, which exhibits comparable biological effects to carbon black or relevant ambient air particles. 

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