Enhancement of peroxisomal enzymes, cytochrome P-452 and DNA synthesis in putative preneoplastic foci of rat liver treated with the peroxisome proliferator nafenopin

The peroxisome proliferator (PP) nafenopin (NAF) enhanced tumordevelopment in rat liver through promotion of a subtype of putativepreneoplastic cell foci, characterized by weak cytoplasmic basophilia(1,2). In order to elucidate the selective growth advantageof these weakly basophilic foci (WBF) we investigated the effectsof NAF on their metabolic phenotype and DNA synthesis. In WBF,as well as in other foci subpopulations and in hepatocellularcarcinomas the occurrence of five NAF-inducible enzymes, i.e.of peroxisomal ß-oxidation (acyl-CoA oxidase, bifunctionalprotein and thiolase), catalase and cytochrome P-452 was studiedby immunohistochemical methods. In untreated livers almost allfoci were stained with the same intensity as the surroundingtissue. When NAF was applied, most of the liver foci showedconsiderably less staining than the non-focal parenchyma inwhich pronounced enzyme induction had occurred. However, thesubpopulation of WBF showed a more heterogeneous pattern ofenzyme expression varying from less to even more than in theadjacent tissue. A similarly broad range of expression of peroxisomalenzymes was found in hepatocellular carcinomas. On average,however, the tumors exhibited less staining and lower activityof peroxisomal ß-oxidation than the surrounding parenchyma.WBF always showed higher rates of DNA synthesis than other focisubtypes and unaltered liver. In     

2,4,6-triarylchalcogenopyrylium dyes related in structure to the antitumor agent AA1 as in vitro sensitizers for the photodynamic therapy of cancer.

Cationic chalcogenopyrylium dyes 2-4 were synthesized in six steps from 4-(dimethylamino)phenylethyne (7), have absorption maxima in methanol of 594, 631, and 672 nm, respectively, and generate singlet oxygen with quantum yields [Phi((1)O(2))] of 0.020, 0.064, and 0.037, respectively. Dyes 2-4 are hydrolytically more stable than other chalcogenopyrylium dyes evaluated previously as sensitizers for photodynamic therapy. At 10 microM final concentration, all dyes 2-4 inhibited cytochrome c oxidase during irradiation of tumor mitochondrial suspensions treated with 10 microM dye. The degree of enzyme inhibition was abated in a reduced oxygen environment and in the presence of imidazole, a singlet oxygen trap. Superoxide dismutase, at a final concentration of 30 U, did not alter the photosensitized inhibition of mitochondrial cytochrome c oxidase by dyes 2-4. These data suggest that singlet oxygen may play a major role in the photosensitized inhibition of mitochondrial cytochrome c oxidase. Irradiation of R3230AC rat mammary adenocarcinoma cells in the presence of dyes 2-4 caused a significant loss in cell viability with thiopyrylium dye 2 displaying the greatest phototoxicity. Initial acute toxicity studies in vivo demonstrate that, at 10 mg/kg, none of the three dyes displayed overt toxicity.     

11 November 1979--a day to remember: the Mississauga disaster

The derailment of a train carrying potentially lethal chlorine, accompanied by exploding tank cars of propane, set into motion the evacuation of the Mississauga Hospital, Queensway General Hospital (Etoblcoke), and Oakville-Trafalgar Memorial Hospital, near Toronto. The method in which the three hospitals, along with the 220,000 residents of Mississauga, were evacuated was so highly efficient and orderly that many now question the necessity of the action. But absence of panic should not be interpreted as an absence of danger. The Economist (17 - 23 November, 1979, volume 273, number 7107) extrapolated data from a British study to show there was enough chlorine in the tank to kill 24,000 people, given the population density in the area of the derailment. The purpose of this article is to describe the involvement of hospital pharmacy in the "Mississauga Saga", and to draw some conclusions from this experience.     

Studies on the stability of trimelamol, a carbinolamine-containing antitumor drug

The stability of trimelamol (N2,N4,N6-trimethylol-N2,N4,N6-trimethylmelamine) a synthetic carbinolamine-containing antitumor drug, has been studied. Two major degradation pathways have been characterized and a unified mechanism proposed to rationalize the chemistry involved. One degradation pathway involves the consecutive loss of hydroxymethylene units by elimination of formaldehyde until the parent trimethylmelamine (4) results. An HPLC method was used to obtain kinetic data for the loss of trimelamol and to monitor the order of appearance of three degradation products. This pathway was shown to follow first-order kinetics at all pH values studied at both 18 and 37 degrees C. The second pathway involves the coupling of two trimelamol molecules via a methylene bridge to form bis(trimelamol) (6) which had been previously referred to in the literature as a "polymer". This reaction is acid catalyzed and temperature dependent. Bis(trimelamol) is virtually water insoluble and adheres strongly to glass surfaces. Finally, t1/2 values have been determined for trimelamol in aqueous solution at different temperatures, and the kinetics of formation of degradation products has been studied over a period of 30 h under a variety of conditions of pH and temperature. The data reported here are relevant to both the formulation and clinical administration of trimelamol, and may contribute to an understanding of mechanism of action and future analogue development studies.     

The cellular basis of delirium and its relevance to age-related disorders including Alzheimer's disease.

A wide variety of conditions lead to delirium (i.e., metabolic encephalopathies) in human beings and animals. Despite the varied etiology the clinical consequences are relatively stereotyped which suggests that the diverse insults that cause delirium may act by common metabolic and cellular "final pathways." Related molecular and cellular mechanisms may be involved in aging and Alzheimer's disease, conditions that predispose to the development of delirium. Animal models of delirium better reflect age-related disorders such as Alzheimer's disease than those that impair a single neurotransmitter system such as the cholinergic system; the metabolic encephalopathies produce global cognitive disturbance, which is more typical of these disorders. Thus, research related to delirium has far-reaching implications for normal and abnormal brain function.