Curcumin, bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione, is a natural yellow-orange dye derived from the rhizome of Curcuma longa, an East Indian plant. In order to understand the photobiology of curcumin better we have studied the spectral and photochemical properties of both curcumin and 4-(4-hydroxy-3-methoxy-phenyl)-3-buten-2-one (hC, half curcumin) in different solvents. In toluene, the absorption spectrum of curcumin contains some structure, which disappears in more polar solvents, e.g. ethanol, acetonitrile. Curcumin fluorescence is a broad band in acetonitrile (lambda max = 524 nm), ethanol (lambda max = 549 nm) or micellar solution (lambda max = 557 nm) but has some structure in toluene (lambda max = 460, 488 nm). The fluorescence quantum yield of curcumin is low in sodium dodecyl sulfate (SDS) solution (phi = 0.011) but higher in acetonitrile (phi = 0.104). Curcumin produced singlet oxygen upon irradiation (lambda > 400 nm) in toluene or acetonitrile (phi = 0.11 for 50 microM curcumin); in acetonitrile curcumin also quenched 1O2 (kq = 7 x 10(6) M-1 s-1). Singlet oxygen production was about 10 times lower in alcohols and was hardly detectable when curcumin was solubilized in a D2O micellar solution of Triton X-100. In SDS micelles containing curcumin no singlet oxygen phosphorescence could be observed. Curcumin photogenerates superoxide in toluene and ethanol, which was detected using the electron paramagnetic resonance/spin-trapping technique with 5,5-dimethyl-pyrroline-N-oxide as a trapping agent. Unidentified carbon-centered radicals were also detected.(ABSTRACT TRUNCATED AT 250 WORDS)

Gram-negative and gram-positive bacteria were found to display different sensitivities to pure singlet oxygen generated outside of cells. Killing curves for Salmonella typhimurium and Escherichia coli strains were indicative of multihit killing, whereas curves for Sarcina lutea, Staphylococcus aureus, Streptococcus lactis, and Streptococcus faecalis exhibited single-hit kinetics. The S. typhimurium deep rough strain TA1975, which lacks nearly all of the cell wall lipopolysaccharide coat and manifests concomitant enhancement of penetration by some exogenous substances, responded to singlet oxygen with initially faster inactivation than did the S. typhimurium wild-type strain, although the maximum rates of killing appeared to be quite similar. The structure of the cell wall thus plays an important role in susceptibility to singlet oxygen. The outer membrane-lipopolysaccharide portion of the gram-negative cell wall initially protects the bacteria from extracellular singlet oxygen, although it may also serve as a source for secondary reaction products which accentuate the rates of cell killing. S. typhimurium and E. coli strains lacking the cellular antioxidant, glutathione, showed no difference from strains containing glutathione in response to the toxic effects of singlet oxygen. Strains of Sarcina lutea and Staphylococcus aureus that contained carotenoids, however, were far more resistant to singlet oxygen lethality than were both carotenoidless mutants of the same species and other gram-positive species lacking high levels of protective carotenoids.

Curcumin is a yellow-orange compound derived from the root of Curcuma longa (Zingiberaceae family), that has been used as a medicine, spice and coloring agent. Curcumin has proved nontoxic in a number of cell culture and whole animal studies. Curcumin has, however, been reported to have bactericidal effects at very high concentrations. When illuminated, curcumin exerted potent phototoxic effects in micromolar amounts. Gram-negative bacteria displayed greater resistance to curcumin phototoxicity relative to Gram-positive bacteria. Oxygen was required for curcumin phototoxicity. Curcumin binding to cells was not required for photokilling; the reactive intermediate therefore must be relatively long-lived. The mechanism(s) of curcumin phototoxicity may involve hydrogen peroxide production. Singlet excited oxygen was not detected.

Curcumin, bis(4-hydroxy-3-methoxyphenyl)-1,6-diene-3,5-dione, is a yellow-orange dye derived from the rhizome of the plant Curcuma longa. Curcumin has demonstrated phototoxicity to several species of bacteria under aerobic conditions (Dahl, T. A., et al., 1989, Arch. Microbiol. 151 183), denoting photodynamic inactivation. We have now found that curcumin is also phototoxic to mammalian cells, using a rat basophilic leukemia cell model, and that this phototoxicity again requires the presence of oxygen. The spectral and photochemical properties of curcumin vary with environment, resulting in the potential for multiple or alternate pathways for the exertion of photodynamic effects. For example, curcumin photogenerates singlet oxygen and reduced forms of molecular oxygen under several conditions relevant to cellular environments. In addition, we detected carbon-centered radicals, which may lead to oxidation products (see accompanying paper). Such products may be important reactants in curcumin's phototoxicity since singlet oxygen and reduced oxygen species alone could not explain the biological results, such as the relatively long lifetime (t1/2 = 27 s) of the toxicant responsible for decreased cell viability.

Purpose: STA-4783 is a new compound that markedly enhances the therapeutic index of paclitaxel against human tumor xenograft models. A phase I clinical trial was undertaken to determine the maximum tolerated dose, toxicity profile, and pharmacokinetics of STA-4783 in combination with paclitaxel. Experimental Design: Adults with refractory solid tumors concurrently received STA-4783 and paclitaxel as a 3-h i.v. infusion at starting doses of 44 and 135 mg/m 2 , respectively. After increasing paclitaxel to 175 mg/m 2 , the STA-4783 dose was escalated as permitted by dose-limiting toxicity during the first 21-day cycle. Results: Thirty-five patients were treated with eight dose levels of STA-4783/paclitaxel. In patients receiving 175 mg/m 2 paclitaxel, the incidence of severe toxicity increased with escalation of the STA-4783 dose above 263 mg/m 2 , and 438 mg/m 2 was the maximum tolerated dose. All toxicities were typical of paclitaxel, with neutropenia, mucositis, and myalgia/arthralgia being dose limiting. Partial responses were achieved in one patient with Kaposi's sarcoma and another with ovarian cancer that progressed during prior treatment with paclitaxel. STA-4783 exhibited linear pharmacokinetics characterized by rapid elimination from plasma (biological half-life, 1.06 F 0.24 h) and a low steady-state apparent volume of distribution (25.1 F 8.1L/m 2 ). The total body clearance of paclitaxel decreased significantly with escalation of the STA-4783 dose. Conclusions: The STA-4783/paclitaxel combination was well tolerated with a toxicity profile similar to single-agent paclitaxel. Enhanced systemic exposure to paclitaxel resulting from a dose-dependent interaction with STA-4783 was associated with increased toxicity. Objective responses in two heavily pretreated patients, both with taxane exposure, have encouraged further clinical evaluation of this regimen.

A variety of supported metal and metal oxide adsorbents were evaluated for removal of arsine (AsH 3 ) from synthesis gas (syngas), a mixture primarily of carbon monoxide and hydrogen. A copper(II) oxide (CuO)/ carbon adsorbent was judged to be most promising and examined more thoroughly. Exposure of the CuO/ carbon adsorbent to syngas at 750 psig resulted in only a modest increase in bed temperature. No evidence that the adsorbent acted as a methanol synthesis catalyst or promoted other syngas chemistry was observed. It was found, however, that even at modest temperatures (30-40 °C) some reduction to metallic copper (Cu) occurred. The exothermic reduction of CuO presented a significant operational concern, and use of the adsorbent required a controlled reduction to Cu/carbon prior to exposure to syngas. The arsine affinity of CuO/carbon was very high with a minimum capacity of 3.0 wt % arsenic for a syngas feed containing 420 ppbv. The reduced adsorbent, Cu/carbon, was less effective for AsH 3 removal, and at 30 °C its capacity was 1.74 wt %. Operation at 140 °C resulted in more effective AsH 3 removal with a minimum arsenic capacity of 4.31 wt % for a feed gas containing 737 ppbv AsH 3 . The kinetic limitation for AsH 3 adsorption at near ambient temperature is likely the result of slow migration of arsenic from the copper surface. At 140 °C arsenic migration is fast enough to provide a clean copper surface for adsorption. The Cu/carbon adsorbent was slightly less effective for phosphine removal than for AsH 3 . The sulfur-containing contaminants thiophene, carbonyl sulfide, and carbon disulfide were only partially removed from a syngas feed, and the adsorbent had almost no affinity for methyl chloride.

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Abskact-The photodynamic inactivation by illuminated Rose Bengal of a number of bacterial species was compared. The gram-positive species, Bacillus subtilis, Staphylococcus nureus, Streptococcus faecalis and Streptococcus salivarius, were inactivated about 200X more quickly (99% inactivation) than a Salmonella typhimurium wildtype strain. The Salmonella inactivation curve exhibited an initial lag time during which bacteria were not significantly inactivated. The lag time for inactivation of a derivative of the wildtype Salmonelln strain that is deficient in a large portion of its cell wall lipopolysaccharide coat was approximately half of the lag time for the wildtype strain but the subsequent rate of inactivation was approximately the same for the two strains. Dark preincubation of both Salmonella strains with Rose Bengal before illumination shortened the lag time, but did not increase the final rate of inactivation. Dark preincubation prior to illumination did not measurably change the inactivation curve of the gram-positive species. The lag time observed in the inactivation curves for Salmonella bacteria may reflect the time required for penetration of the Rose Bengal anion through the outer portion of the gram-negative cell wall to a critical location within the cell for effective photosensitization.