Toxicity and Environmental Risk Assessment of Polycarbamate and Its Main Components to Marine Algae and Crustaceans.

Polycarbamate is commonly used as an antifoulant coating on fishing nets in Japan. Although its toxicity to freshwater organisms has been reported, its toxicity to marine organisms is currently unknown. We conducted algal growth inhibition and crustacean immobilization tests to assess the effects of polycarbamate on marine organisms. We also evaluated the acute toxicity of the main components of polycarbamate, namely, dimethyldithiocarbamate and ethylenebisdithiocarbamate, to algae, which are the most sensitive tested organisms to polycarbamate. The toxicities of dimethyldithiocarbamate and ethylenebisdithiocarbamate partially explain that of polycarbamate. To assess the primary risk, we derived the predicted no-effect concentration (PNEC) for polycarbamate in a probabilistic manner using species sensitivity distributions. The 72 h no observed effect concentration (NOEC) of polycarbamate to the alga Skeletonema marinoi-dohrnii complex was 0.45 µg/L. The toxicity of dimethyldithiocarbamate may have contributed up to 72% of the toxicity observed for polycarbamate. The fifth percentile of hazardous concentration (HC5) derived from the acute toxicity values was 0.48 µg/L. Comparison of previously reported environmental polycarbamate concentrations in Hiroshima Bay, Japan, to the PNEC estimated using the minimum NOEC and HC5 suggest that polycarbamate currently poses a high ecological risk. Therefore, reducing the risk by restricting polycarbamate use is necessary.

Chemical treatment of chelated metal finishing wastes.

This study evaluated two chemical approaches for treatment of commingled cadmium-cyanide (Cd-CN) and zinc-nickel (Zn-Ni) wastewaters. The first approach, which involved application of sodium hypochlorite (NaOCl), focused on elimination of chelating substances. The second approach evaluated the use of sodium dimethyldithiocarbamate (DMDTC) to specifically target and precipitate regulated heavy metals. Results demonstrated that by maintaining a pH of 10.0 and an oxidation-reduction potential (ORP) value of +600 mV, NaOCl treatment was effective in eliminating all chelating substances. Cadmium, chromium, nickel, and zinc solution concentrations were reduced from 0.27, 4.44, 0.06, and 0.10 ppm to 0.16, 0.17, 0.03, and 0.06 ppm, respectively. Similarly, a 1% DMDTC solution reduced these same metal concentrations in commingled wastewater to 0.009, 1.142, 0.036, and 0.320 ppm. Increasing the DMDTC concentration to 2% improved the removal of all regulated heavy metals except zinc, the removal of which at high pH values is limited by its amphotericity.

Demonstration of N,N-Dimethyldithiocarbamate as a Copper-Dependent Antibiotic against Multiple Upper Respiratory Tract Pathogens.

Transition metals are necessary cofactors and structural elements in living systems. Exposure to high concentrations of biologically important transition metals, such as zinc and copper, results in cell toxicity. At the infection site, the immune system deploys metal sorbent proteins (e.g., lactoferrin and calprotectin) to starve pathogens of necessary metals (such as iron), while phagocytes expose engulfed pathogens to high levels of other metals, such as copper and zinc. The opportunistic pathogen Streptococcus pneumoniae (the pneumococcus) encounters macrophages during initial and protracted infections. The pneumococcus employs a copper export pathway, which improves colonization and persistent infection of the nasopharynx and the upper respiratory tract. Because copper is tightly regulated in the host, we instead sought to leverage the localized power of nutritional immunity by identifying small molecules with copper-dependent toxicity (CDT) through a targeted screen of compounds for antibiotic efficacy. We chose to include dithiocarbamates, based on the copper synergy observed in other organisms with 1-(diethylthiocarbamoyldisulfanyl)-N,N-diethyl-methanethioamide (tetraethylthiuram disulfide, disulfiram). We observed CDT of some dithiocarbamates in S. pneumoniae. Only N,N-dimethyldithiocarbamate (DMDC) was consistently toxic across a range of concentrations with copper both in vitro and in vivo against the pneumococcus. We also observed various degrees of CDT in vitro using DMDC in Staphylococcus aureus, Coccidioides posadasii, and Schistosoma mansoni. Collectively, we demonstrate that the compound DMDC is a potent bactericidal compound against S. pneumoniae with antimicrobial efficacy against bacterial and fungal pathogens. IMPORTANCE With the rise of antibiotic resistance, approaches that add new antimicrobials to the current repertoire are vital. Here, we investigate putative and known copper ionophores in an attempt to intoxicate bacteria and use ionophore/copper synergy, and we ultimately find success with N,N-dimethyldithiocarbamate (DMDC). We show that DMDC has in vitro efficacy in a copper-dependent manner and kills pathogens across three different kingdoms, Streptococcus pneumoniae, Coccidioides posadasii, and Schistosoma mansoni, and in vivo efficacy against S. pneumoniae. As such, dithiocarbamates represent a new potential class of antimicrobials and thus warrant further mechanistic investigation.

An updated study of mortality among North American synthetic rubber industry workers.

This study evaluated mortality rates from leukemia and other diseases during the time period 1944 through 1998 among 17,924 men employed in the synthetic rubber industry. In this group, there were 6237 deaths, which is 14% fewer than the 7242 deaths expected based on general population rates. Numbers of observed versus expected deaths (shown hereafter as observed/expected) were 1608/1741 for all cancers combined, including 71/61 for leukemia, 53/53 for non-Hodgkin lymphoma (NHL*), and 26/27 for multiple myeloma. The higher than expected number of deaths from leukemia (16% increase) was concentrated in workers paid hourly who had started work 20 to 29 years earlier, had worked 10 or more years in the industry, and had worked in subgroups employed in polymerization, coagulation, maintenance labor, and laboratory operations. The overall higher leukemia mortality rate, as well as the higher rate in the subgroup of hourly workers who had 20 or more years since hire and 10 or more years worked, was not limited to a particular form of leukemia. Cumulative exposure to 1,3-butadiene (BD) was associated positively with all leukemias, with chronic myelogenous leukemia and, to a lesser extent, with chronic lymphocytic leukemia (CLL). Exposure to styrene or to dimethyldithiocarbamate (DMDTC) also was associated positively with leukemia. Exposures to these two agents were correlated with exposure to BD; data were limited on the independent effects of each of the three chemicals on leukemia. After controlling for the effects of BD, we found no consistent exposure-response relation between either styrene or DMDTC and all leukemias, chronic myelogenous leukemia, or CLL. However, a positive association between any exposure to DMDTC and leukemia persisted. The data from this study indicate that employment in the synthetic rubber industry is related causally to leukemia. Uncertainty remains about the specific agent or agents responsible for the association. The carcinogenic mechanisms through which BD, styrene, or DMDTC could cause leukemia in humans have not been established, and epidemiologic support for a leukemogenic role is limited for these agents. Styrene and DMDTC were associated positively with NHL. External support for this relation has not been reported from other epidemiologic studies. The study did not find any clear relation between exposure to BD, styrene, or DMDTC and multiple myeloma. Some subgroups of subjects had more than the expected number deaths from colorectal cancer, prostate cancer, and other diseases. These increases did not appear to be related to occupational exposure in the industry.

Neurotoxicity and behavioral effects of thiram in rats.

Eight of 24 female rats fed 66.9 mg/kg-day of thiram developed neurotoxicity. The neurotoxic effects were characterized by ataxia and paralysis of the hind legs. There were demyelination, degeneration of the axis cylinders, and presence of macrophages in the nerve bundle of the sciatic nerve. Degeneration in the ventral horn of the lower lumbar region of the spinal cord was evidenced by chromatolysis of motorneurons, pyknosis, and satellitosis. During a second experiment, 4 of 24 females fed 65.8 mg/kg--day also developed ataxia and paralysis. An additional 9 females showed clasping of the hind feet when picked up by the tail. Nerve conduction could not be measured for one severely ataxic rat and the electromyogram indicated a loss of motor unit function. Histopathology of this rat, along with the others, suggests the peripheral nerve as the primary site of the lesion. Thiram also caused behavioral changes in apparently normal rats. The walking pattern of the hind legs was altered with decreases in stride width and the angle between contralateral steps. These rats required significantly more shock-motivations and cleared a lower height in a jump/climb ability test. An open-field study indicated that thiram caused hyperactivity in the nonataxic rats of both sexes. Three of 24 rats fed 95.8 mg/kg-day of ferbam also developed ataxia or paralysis.

Studies of enzyme-catalyzed modification of proteins. I. Tyrosinase-catalyzed modification of asparaginase.

Asparaginase [EC 3.5.1.1.] of Escherichia coli, an anti-tumor enzyme, was inactivated in a time-dependent fashion by mushroom tyrosinase [EC1.14.18.1.]. The inactivation did not proceed, however, when heat-inactivated tyrosinase was used. Exculusion of the atmospheric oxygen or addition of diethyldithiocarbamate, a copper selective chelating agent, prevented the inactivation. The difference absorption spectrum of tyrosinase-inactivated asparaginase versus intact asparaginase exhibited the appearance of marked absorption peaks at 300 and 350 nm. These results indicate that the tyrosyl residue(s) of asparaginase, which is essential for the activity is enzymatically modified by tyrosianes.

Enzymological characterization of EpoA, a laccase-like phenol oxidase produced by Streptomyces griseus.

Laccase is an enzyme that catalyzes the oxidation of phenolic compounds by coupling the reduction of oxygen to water. While many laccases have been identified in plant and fungal species, enzymes of prokaryotic origin are poorly known. Here we report the enzymological characterization of EpoA, a laccase-like extracytoplasmic phenol oxidase produced by Streptomyces griseus. EpoA was expressed and purified with an Escherichia coli host-vector system as a recombinant protein fused with a C-terminal histidine-tag (rEpoA). Physicochemical analyses showed that rEpoA comprises a stable homotrimer containing all three types of copper (types 1-3). Various known laccase substrates were oxidized by rEpoA, while neither syringaldazine nor guaiacol served as substrates. Among the substrates examined, rEpoA most effectively oxidized N,N-dimethyl-p-phenylenediamine sulphate with a Km value of 0.42 mM. Several metal chelators caused marked inhibition of rEpoA activity, implying the presence of a metal center essential for the oxidase activity. The pH and temperature optima of rEpoA were 6.5 and 40 degrees C, respectively. The enzyme retained 40% activity after preincubation at 70 degrees C for 60 min. EpoA-like activities were detected in cell extracts of 8/40 environmental actinomycetes strains, which suggests that similar oxidases are widely distributed among this group of bacteria.

Dithiocarbamate-induced redistribution and increased brain uptake of lead in rats.

The effects of dithiocarbamates on brain uptake and tissue distribution of 203Pb were studied in rats injected intravenously with 100 microCi of 203Pb (28.6 nmol/kg b.wt.) as lead acetate. The dithiocarbamates--sodium diethyldithiocarbamate (DEDTC), tetraethylthiuram disulphide (disulfiram), sodium dimethyldithiocarbamate (DMDTC) and tetramethylthiuram disulphide (thiram)--were administered perorally in doses of 2 mmol/kg. Half of the dose was given 2h before and half immediately after the injection of 203Pb. The concentration of 203Pb in tissues, plasma and erythrocytes, and in urine and feces was determined by gamma counting. Four hours after injection of 203Pb, the dithiocarbamate-treated rats had a significantly higher concentration of lead in brain, liver and lung and a significantly lower concentration of lead in kidney, femur and erythrocytes compared to controls. At 72 h the brain concentration of lead in rats administered thiram, DMDTC, disulfiram or DEDTC was 100, 15, 10, and 4 times higher respectively, than in controls. At 72 h these rats also had higher levels of lead in liver, lung and kidney than did controls. The kidneys of dithiocarbamate-treated rats had a higher concentration of lead at 72 h than at 4 h, and during this time the lead concentration in femur had increased in the treated groups as well as in the controls. Excretion was mainly via feces. In controls about 15% of the dose was excreted in feces at 72 h. Fecal excretion at 72 h in DEDTC and DMDTC-treated rats was about 25% and in thiram and disulfiram-treated rats about 7% of the dose. The total urinary excretion of lead at 72 h was about 9% of the dose in controls, 5% in the DEDTC and DMDTC-treated groups and about 1% in the thiram and disulfiram-treated groups. The results indicate that a lipid-soluble complex between lead and the dithiocarbamates is formed in vivo and that these complexes have a high capacity to penetrate the blood-brain barrier and be retained in brain due to binding to lipid rich brain constituents. The toxicity of the complexes is not known, but it is possible that there is intracellular release of inorganic lead after metabolism/decomposition of the complex.

Enhancement of cytotoxicity of bleomycin by dithiocarbamates: formation of bis(dithiocarbamato) cu(II).

Properties of the reactions of dithiocarbamates and their Cu(II) or Fe(III) complexes with Ehrlich cells were determined and related to their effects on the inhibition of cell proliferation caused by bleomycin and Cu bleomycin. In complete culture medium containing Eagle's minimal essential medium plus Earles salts and 2.5% fetal calf serum, dimethyl- and diethyldithiocarbamates and their copper complexes inhibit cell proliferation and cause cell death. The copper complexes are more effective agents. Ferric tris-diethyldithiocarbamate is also a cytotoxic species. In contrast, when cells are exposed to dimethyldithiocarbamate or its copper complex in Ringer's buffer under metal-restricted condition, washed, and then placed in complete medium, the copper complex is much more active in inhibiting cell growth. The difference is magnified when dihydroxyethyldithiocarbamate and N-methylglucamine dithiocarbamate and their copper complexes are compared in complete media. Incubation of bleomycin or copper bleomycin with Ehrlich cells in Ringer's buffer with or without dimethyldithiocarbamate or bis-dimethyldithiocarbamato Cu(II) leads to no enhancement of cytotoxicity from combinations of agents, except when the two copper complexes are present. Diethyl- or dimethyldithiocarbamate readily extracts copper from Cu(II)bleomycin and iron from Fe(III)bleomycin when ethylacetate is present to remove the tris-dithiocarbamato Fe(III) complex from aqueous solution. When bis-dimethyldithiocarbamato Cu(II) is incubated with Ehrlich cells, copper is released from the complex and bound to high molecular weight and metallothionein fractions. A reductive mode of dissociation of the copper complexes in cells is supported by ESR experiments. Reactions of diethyl- and dimethyldithiocarbamato Cu(II) with thiol compounds demonstrates one possible mechanism of reduction of these complexes.

Effect of thiram and dithiocarbamate pesticides on the gastrointestinal absorption and distribution of nickel in mice.

Oral administration of dimethyldithiocarbamate pesticides (ferbam, ziram or sodium dimethyldithiocarbamate) or thiram together with nickel resulted in increased levels of the metal in several tissues of rats, in comparison with animals given only nickel. In contrast, the administration of nickel together with ethylene- or propylenebisdithiocarbamates (zineb, maneb, nabam or propineb) resulted in unchanged tissue levels or, most marked for nabam, reduced the tissue concentrations of the metal. Among the compounds which were able to increase tissue levels of nickel, thiram was the most effective one, followed in decreasing order by ferbam, ziram and sodium dimethyldithiocarbamate. The central nervous system was among the tissues which showed the highest relative increase. For thiram, an accumulation of nickel was observed in the pancreatic islets. The results are discussed in relation to the formation of chelates between nickel and the studied compounds or their metabolites.

Activities of hepatic epoxide hydrolase and glutathione S-transferase in rats under the influence of tetramethyl thiuramdisulfide, tetramethyl thiurammonosulfide or dimethyl dithiocarbamate.

The epoxide hydrolase (EH) activity in the liver of adult female Wistar rats significantly increased 18 h after the administration by gavage of tetramethyl thiuramdisulfide (TMTD, 1 mmol/kg) or tetramethyl thiurammonosulfide (TMTM, 2 mmol/kg). No increase was observed 5 h after administration of Na-dimethyl dithiocarbamate (Na-DMDTC, 4 mmol/kg). The glutathione S-transferase (GST) activity in the cytosol and microsomes of the liver was slightly enhanced after oral (gavage) administration of TMTD, TMTM or Na-DMDTC (doses up to 4 mmol/kg). In vitro, TMTD, TMTM, and Na-DMDTC significantly enhanced the hepatic activity of EH prepared from adult female Wistar rats. Cytosolic and microsomal GST activities from the liver were significantly raised in vitro by Na-DMDTC. The results have a bearing on the evaluation of the risk to health of these chemicals in the workplace.

Photoinhibition of photosystem I is accelerated by dimethyldithiocarbamate, an inhibitor of superoxide dismutase, during light-chilling of spinach leaves.

In vivo photoinhibition of photosystem I (PS I) was investigated at chilling temperature using the leaves of the chilling-resistant spinach plant treated with an inhibitor of superoxide dismutase, diethyldithiocarbamate (DDC). When spinach leaves were treated with DDC during chilling at 4 degrees C for 12 h with a light intensity of 120 micromol m(-2) s(-1), the activity of PS I and the content of iron-sulfur centers declined to about 50% and 25% of the non-DDC-treated controls, respectively. A native green gel analysis of thylakoid membranes isolated from the DDC-treated leaves resolved a novel chlorophyll-protein complex, which was identified as the light-harvesting complex I (LHC I)-deficient PS I complex when examined by 77 K fluorescence spectroscopy and two-dimensional sodium dodecyl sulfate gel electrophoresis. The possible dissociation of LHC I as an early structural change in the PS I complex after DDC-induced photoinhibition of PS I is discussed.

In vitro antimicrobial activity of diethyldithiocarbamate and dimethyldithiocarbamate against methicillin-resistant Staphylococcus.

Staphylococcus aureus has appeared which is highly resistant to both methicillin and aminoglycosides. Current therapy involves long-term intravenous therapy of vancomycin. Since vancomycin is currently the only drug used to treat these patients, there is a need to develop additional antimicrobial therapy. The in vitro antimicrobial effect of the metal chelator, diethyldithiocarbamate (DDTC) and its structural analog dimethyldithiocarbamate (DMTC) were investigated. Both DDTC and DMTC were effective against S. aureus including methicillin-resistant S. aureus (MRSA). By agar diffusion, DDTC at 10 micrograms per disk produced zone sizes of 12 to 21 mm and at 100 micrograms per disk produced zone sizes of 26 to 34 mm against MRSA. The DMTC produced slightly greater zone sizes against MRSA of 16 to 24 mm and 24 to 37 mm for 10 micrograms per disk and 100 micrograms per disk, respectively. The minimum inhibitory concentration (MIC) for DMTC against MRSA was 6 micrograms per ml. Both DDTC and DMTC were also effective against enterococci, Proteus mirabilis, Klebsiella pneumoniae, Klebsiella oxytoca, Escherichia coli, Enterobacter cloacae, Enterobacter aerogenes, Salmonella species, Serratia marcescens and Citrobacter freundii at 100 micrograms per disk. The MICs of DMTC for Klebsiella pneumoniae, Klebsiella oxytoca, Escherichia coli, Salmonella and Citrobacter freundii were approximately 128 micrograms per ml while the MICs for Proteus vulgaris, Proteus mirabilis, Pseudomonas aeruginosa and Serratia marcescens was greater than or equal to 256 micrograms per ml. In addition, DMTC was synergistic with gentamicin against MRSA and coagulase-negative staphylococcus species, Enterobacter cloacae, Klebsiella pneumoniae and Pseudomonas aeruginosa. Additive and synergistic effects of DMTC were displayed with gentamicin against S. aureus including methicillin-resistant S. aureus.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanism of diethyldithiocarbamate, dihydroxyethyldithiocarbamate, and dicarboxymethyldithiocarbamate action of distribution and excretion of cadmium.

Diethyldithiocarbamate (DEDC), dihydroxyethyldithiocarbamate (DHDC), and dicarboxymethyldithiocarbamate (DCDC) were assessed for their relative efficacies in mobilizing metallothionein-bound cadmium (Cd) from selected organs and tissues of mice and in promoting Cd excretion. The DHDC was effective but less so than DEDC in mobilizing Cd from liver, kidney and spleen. However, while DEDC effected a redistribution of Cd which resulted in higher levels in lungs, testes, heart, and brain, DHDC after 13 injections reduced the levels of Cd in all four of these organs. The DCDC analog did not alter the Cd load of any organ. Bone Cd content was most effectively reduced by DEDC; DCDC was somewhat less active, and DCDC was without effect. Skin Cd burden was enhanced markedly after treatment with DEDC but was reduced by treatment with DHDC or DCDC. Treatment with DEDC increased the muscle Cd content about 250 percent over control values; treatment with DHDC reduced it significantly, while DCDC was without effect. Both DEDC and DHDC reduced the whole body Cd burden, but DCDC was ineffective. The initial rate of fecal excretion of Cd was much greater following DHDC treatment than after DEDC treatment, while DCDC did not promote excretion to any detectable extent. The pattern of mobilization, redistribution, and excretion of Cd following treatment with each chelator was related to the organic/aqueous partition coefficient of each dithiocarbamate-Cd complex.

In vitro studies with dimethyldithiocarbamate, possible new antimicrobial for use in poultry.

Tests were conducted to determine the in vitro efficacy of the dithiocarbamate analogue, dimethyldithiocarbamate (DmDTC), against selected poultry pathogens. Organisms studied were two bacteria, Pasteurella multocida and Escherichia coli, and a mold, Aspergillus fumigatus. Zone of inhibition and the minimum inhibitory concentration were determined for each organism. DmDTC was effective in vitro against all organisms tested, with A. fumigatus showing greatest overall sensitivity.

Effect of dithiocarbamates on citric acid production by Aspergillus niger.

Dithiocarbamates were found to enhance the production of citric acid under solid-state fermentation conditions by Aspergillus niger. Maximum increase was observed with tetramethylthiuram disulfide (TMTD). Percent increases observed were 74.2% with 2.5 micrograms/mL of TMTD, 19.6% with 2.5 micrograms/mL of sodium dimethyldithiocarbamate and 33.1% with 0.6 micrograms/mL of zinc dimethyldithiocarbamate.

[Biogenic amine metabolism in homeotherms exposed to pesticides of different chemical nature]. / Osobennosti obmena biogennykh aminov u teplokrovnykh pri vozdeistvii pestitsidami razlichnoi khimicheskoi prirody.

Some aspects of the biogenic amines -- serotonin and histamine metabolism in rats and guinea pigs following introduction to them of pesticides of different chemical nature, viz. gamma-isomer of hexachlorcyclohexane (lindane) and dimethyldithiocarbamate zinc (zyram) were studied. These pesticides were found to dissimilarly affect the passage with urine of the principal serotonin metabolite -- 5-oxyindol-acetic acid. A short-term (2 days) introduction to rats of large doses (34 mg/kg) of lindane and a protracted (90 days) action of low doses (1.7 mg/kg) produce changes in the content of serotonin and of 5-oxyindol-acetic acid in the brain, liver and kidneys. In the blood of guinea pigs receiving for a lenthy time (120 days) small amounts (4 mg/kg) of zyram shifts in the histamine-histaminase-histaminopexy system were revealed, this pointing to the ability of this pesticide to provoke the state of sensitization.

Prenatal treatment of mosaic mice (Atp7a mo-ms) mouse model for Menkes disease, with copper combined by dimethyldithiocarbamate (DMDTC).

Menkes disease is a fatal neurodegenerative disorder in infants caused by mutations in the gene ATP7A which encodes a copper (Cu) transporter. Defects in ATP7A lead to accumulated copper in the small intestine and kidneys and to copper deficiencies in the brain and the liver. The copper level in the kidney in postnatal copper-treated Menkes patients may reach toxic levels. The mouse model, mosaic Atp7a (mo-ms) recapitulates the Menkes phenotype and die about 15.75±1.5 days of age. In the present study we found that prenatal treatment of mosaic murine fetuses throughout gestation days 7, 11, 15 and 18 with a combination of CuCl(2) (50 mg/kg) and dimethyldithiocarbamate (DMDTC) (280 mg/kg) leads to an increase in survival to about 76±25.3 days, whereas treatment with CuCl(2) alone (50 mg/kg) only leads to survival for about 21 days ±5 days. These copper-DMDTC treated mutants showed an improved locomotor activity performance and a gain in body mass. In contrast to treatment with CuCl(2) alone, a significant increase in the amount of copper was observed in the brain after prenatal copper-DMDTC treatment as well as a decrease in the amount of accumulated copper in the kidney, both leading towards a normalization of the copper level. Although copper-DMDTC prenatal treatment only leads to a small increase in the sub-normal copper concentration in the liver and to an increase of copper in the already overloaded small intestine, the combined results suggest that prenatal copper-DMDTC treatment also should be considered for humans.

Highly cytotoxic substitutionally inert rhodium(III) tris(chelate) complexes: DNA binding modes and biological impact on human cancer cells.

The antiproliferative properties and cellular impact of novel substitutionally inert rhodium(III) complexes of the types [Rh{(CH3)2 NCS2}2(pp)]Cl 3-5 (pp=5,6-Me2phen, dpq, dppz) and OC-6-23-[Rh(2-S-py)2(pp)]Cl 6 and 7 (2-S-py=pyridine-2-thiolate; pp=dpq, dppz) have been investigated for the adherent human cancer cell lines MCF-7 and HT-29 and for non-adherent Jurkat cells. Whereas CD and viscosity measurements indicate that the polypyridyl ligands of 4 and 5 intercalate into CT DNA, this is not the case for the analogous pyridine-2-thiolate complexes 6 and 7. Complexes 3-7 all exhibit a high antiproliferative activity towards MCF-7 and HT-29 cells, with IC(50) values in the range 0.055-0.285 µM. As established by online monitoring with a cell-based sensor chip, the highly cytostatic complex 6 (IC(50)=0.059 and 0.078 µM) invokes an immediate concentration-dependent reduction of MCF-7 cell respiration and a time-delayed decrease in cellular impedance, which can be ascribed to the induction of cell death. Annexin V/PI assays demonstrated that 6 also has a pronounced antiproliferative activity towards Jurkat cells and that it invokes extensive apoptosis and high concentrations of reactive oxygen species in these leukemia cells. The observation of a dose-dependent inhibition of the oxygen consumption of isolated mice mitochondria indicates the involvement of an intrinsic mitochondrial pathway in this process.