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C Paoletti

Publications and source records attributed to C Paoletti.

At least 109 records · Page 6Linked to original sources
PubMed1979

[Hydroxy 9-methyl 2-ellipticinium acetate (NSC 264-137). Toxicologic study and therapeutic effect in 100 cancers (author's transl)].

A new derivative of ellipticine, hydroxy-9-methyl-2-ellipticinium acetate, was found to be a useful anti-tumor drug in advanced cancers which could not be treated any longer successfully by any other procedure. In our series of 100 patients, the best results were obtained with bone metastases from breast carcinomas and with anaplastic thyroid carcinomas. Most patients usually received a weekly perfusion of 80 mg/m2. The main characteristic of this drug is its lack of hematologic, and hepatic toxicity. No renal trouble was observed during the first year, but 2 deaths from renal insufficiency occured during the 18th and 15th month of treatment. The most frequent side effect consists of digestive troubles (nausea, vomiting) which rarely compelled to stop the treatment (4 times in 100 patients).

Alkaloids↗
PubMed1979

Yeast mitochondrial deoxyribonuclease stimulated by ethidium bromide. 2. Mechanism of enzyme activation.

An endonuclease (EtdBr DNase), which is more active in the presence of EtdBr, has been purified from yeast mitochondrial membrane (Jacquemin-Sablon, H., et al. (1979) Biochemistry 18 (preceding paper in this issue)). This paper deals with the analysis of the mechanism of this activation. Determination of the enzyme activity in the presence of intercalating and nonintercalating agents showed that the enzyme does not recognize the DNA structure modifiction provoked by drug intercalation. Studies carried out with a series of phenanthridinium derivatives led to the following model. The EtdBr DNase activation would result from the formation of a ternary complex, DNA--drug--Triton X-100. The activation capacity of a drug depends on its ability to bind simultaneoulsy to the DNA (not necessarily by intercalation) and the detergent. When this complex is formed, the DNA molecule is surrounded with Triton X-100 molecules which constitute an hydrophobic environment and make the substrate more prone to interaction with the enzyme. The implications of this model are discussed.

Deoxyribonucleases↗
PubMed1979

Ellipticines as potent inhibitors of microsomes-dependent chemical mutagenesis.

9-Hydroxyellipticine (9-OHE), an inhibitor of microsomal monooxygenase activities has been shown to exert a large or even complete decrease of the mutagenicity, on the Salmonella strains of a great number of compounds (aromatic amines, polycyclic aromatic hydrocarbons, fungal toxins, azo compounds, tobacco smoke condensate). 9-OHE and 9-fluoroellipticine are more potent inhibitors than ellipticine itself. The inhibitions exerted by 9-OHE are not even equalled by 10-fold higher doses of 7,8-benzoflavone (7,8-BF). There is a good correlation between these data and the interaction properties of ellipticines with microsomal cytochromes P-450.

Alkaloids↗
PubMed1979

Comparative cytotoxic and antitumoral effects of ellipticine derivatives on mouse L 1210 leukemia.

Twelve derivatives of the antitumoral alkaloid ellipticine (E) and ellipticinium were assayed in vitro on cultured L 1210 cells. These drugs possess varying abilities to decrease the cell growth rate in a 1--1000-fold range. Some of them have a highly cytotoxic effect in the 10(-8)--10(-6) M range. Non-specific intracellular damages are produced: multilobation of nuclei, occurrence of numerous lipid granules, diminution of the size and increase in the number of mitochondrial profiles and several modifications of the internal architecture of mitochondria. 2-Methyl-9-hydroxyellipticinium (2-CH3-9-OHE) was submitted to a bioassay; it inactivates the tumorigenic potency of the cells exposed to it, when they are grafted back into mice in the same dose range which reduces in vitro the growth rate of the cells. A fairly good correlation holds between the in vitro and in vivo (antitumor effect) assays, offering a possible prescreening test for a cheaper and rapid evaluation of chemotherapeutic activity of these compounds. The results stress again the importance of the 9-hydroxy substitution in these series for improving the anticancer efficiency. The nature of the biochemical target of E and derivatives is discussed according to our data.

Alkaloids↗
PubMed1978

Some antitumor derivatives of ellipticine deprived of mutagenic properties.

Seven derivatives of the antitumor alkaloid ellipticine were assayed for activity against murine leukaemia L1210 and for mutagenicity in Ames' Salmonella-microsomes test. Not only did the results show a complete lack of correlation between these two properties, but it was possible to choose a highly efficient analog which was completely devoid of mutagenic and hence, probably, carcinogenic effect. The lack of interaction of this product (2-methyl-9-hydroxyellipticinium acetate) with Cytochrome P-450 of hepatic monooxygenases prevents the formation of reactive intermediates and their subsequent binding to DNA. These data are discussed in view of the currently admitted mode of action of ellipticines i.e., intercalation in DNA and their therapeutic use.

Alkaloids↗
PubMed1977

Histochemical evidence of altered development of cholinergic fibers in the rat dentate gyrus following lesions. II. Effects of partial entorhinal and simultaneous multiple lesions.

It has been concluded previously that the septohippocampal fibers which project to the rat dentate gyrus extend or branch in the denervated area of the molecular layer following a complete ipsilateral entorhinal lesion. The septohippocampal fibers thus appear to replace some of the perforant fibers which degenerate as a result of the lesion. The reactive fibers eventually become localized to a much smaller and more superficial area after lesions of immature rats than after lesions made in adulthood. To determine whether this difference in the response results from a selective reaction to loss of the lateral perforant path in the immature rat, various portions of the entorhinal cortex were removed at the age of 11 days, and the cholinergic septohippocampal fibers were visualized by acetylcholinesterase histochemistry. An alternative possibility, that the difference between immature and adult rats is attributable to an interaction with other reactive afferents, was tested by removing other sources of input (the contralateral entorhinal cortex, contralateral hippocampal formation or both) along with the ipsilateral entorhinal cortex at the age of 11 days and then demonstrating the septohippocampal fibers histochemically. Lesions of the lateral part of the ipsilateral entorhinal cortex (source of the lateral perforant path) at 11 days of age evoked a septohippocampal reaction along the outer edge of the molecular layer, where the lateral perforant path fibers normally terminate. This result matched that produced by a complete entorhinal lesion. Lesions of the medial entorhinal cortex evoked no obvious reaction. In contrast, the septohippocampal fibers in adult rats proliferated in the denervated area of the molecular layer after lesions of either part of the entorhinal cortex. Combining lesions of other sources of innervation to the dentate gyrus with an ipsilateral entorhinal lesion at 11 days of age did not alter the response of septohippocampal fibers, as determined histochemically. Neither did the septohippocampal fibers react to removal of commissural afferents alone. The response at any age was unaffected by prior or subsequent removal of the contralateral entorhinal cortex. These results indicate that in immature rats the septohippocampal fibers respond only to loss of the lateral perforant path, but these same fibers can later react to loss of any part of the perforant path. They are regarded as support for the hypothesis that the reactive septohippocampal fibers preferentially interact with dendritic growth cones. Our results do not support explanations based on a hypothetical attraction between septohippocampal and crossed perforant path fibers (which react in the same area) or on competition with commissural fibers (which reinnervate an adjacent area). We suggest further that proximity to the degenerating elements does not in itself determine the pattern of reinnervation after lesions of the central nervous system.

Acetylcholinesterase↗
PubMed1977

Relative efficiencies of a series of square-planar plantinum(II) compounds on Salmonella mutagenesis.

Twelve Pt(II) compounds have been tested for mutagenicity on Salmonella typhimurium (strain TA 100). Very high mutagenic activities were found for the cis derivatives. A correlation is suggested between these results and a formerly described model of chemical reactivity towards DNA, according to which cis derivatives from intra-strand chelates with guanine. A smaller activity was found with monodentate complexes with DNA.

Binding Sites↗
PubMed1976

Cardiovascular activity of 9-hydroxy-ellipticine.

The cardiovascular activity of 9-hydroxy-ellipticine (9-OH-E) has been studied on anaesthetized dogs. The drug has been administered intravenously in one dose ranging from 1 to 10 mg/kg. The variations in the myocardial contractility, the systemic haemodynamics, the respiration and the general metabolism of the anaesthetized dogs were studied to make evident the mechanism of 9-OH-E cardiostimulating action. 9-OH-E from 5 mg/kg i.v. stimulates the contractility of myocardium and improves the cardiac performances of the anaesthetized dogs. This heart-stimulating action is long-lasting and is not accompanied by any modification in the arterial blood pressure. It is inhibited or at least strongly attenuated by beta-adrenergic blocking agents and by the depletion of catecholamines.

Alkaloids↗
PubMed1976

Antitumor activity of 9-hydroxyellipticine (NSC 210717) ON L1210 mouse leukemia and the effect of route of injection.

The antitumor activity of a new derivative of ellipticine, 9-hydroxyellipticine (NSC 210717), was studied using L1210 mouse leukemia. Low doses of this drug have a high antileukemic activity, whereas high doses have less activity than expected because of a leveling off in the antitumor activity-dose relationship, as if a few cells were resistant to the treatment. The possible causes of this apparent resistance were investigated. It is suggested that this apparent resistance is related to the sequestration of a small number of cells in compartments inaccessible to the drug. A model was developed which takes into account the distribution of cells in various compartments and their drug sensitivity therein. It was predicted and observed that the activity of drugs acting on cells in the small compartments can be observed only in conjunction with the presence of drugs acting on the cells in the major compartment. The importance of this observation in the screening procedures of new drugs, the clinical trial of new chemotherapeutic agents, and the association of anticancer drugs are discussed within this context. 9-Hydroxyellipticine is of interest because it acts on leukemic cells in the brain.

Alkaloids↗
PubMed1975

[2 new antineoplastic derivatives: 9-hydroxy-2-methyl-ellipticinium (acetate) and 9-hydroxy-2,6-dimethyl-ellipticinium (chloride). Effect on mouse L 1210 leukemia].

The antitumoral activity of two new derivatives of ellipticine, 9-hydroxy-2-methyl ellipticinium and 9-hydroxy-2,6-dimethyl-ellipticinium, has been determined using L 1210 mouse leukemia. The first compound elicits a therapeutic index similar to that of 9-hydroxy-ellipticine but is active at doses ten times smaller. The second compound elicits an exceptionally high therapeutic index. It is still active when used at one hundredth of the sublethal dose.

Alkaloids↗