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C Paoletti

Publications and source records attributed to C Paoletti.

At least 91 records · Page 5Linked to original sources
PubMed1983

Autoxidation of the antitumor drug 9-hydroxyellipticine and its derivatives.

In aqueous solution and using molecular oxygen as electron acceptor, the antitumor drug 9-hydroxyellipticine (9-OH-E) undergoes a spontaneous oxidation to give hydrogen peroxide (H2O2), the quinone imine 9-oxoellipticine (9-oxo-E), and a dimer of 9-OH-E(9-OH-E2). Electron paramagnetic resonance (EPR) experiments performed either in alkaline Me2SO or in phosphate buffer in the presence of the spin trap 5,5-dimethylpyrroline 1-oxide (DMPO) suggest that the oxidation process involves the initial formation of superoxide anion (O2- .) and the free radical of the drug. In aqueous medium, this step is followed by the dismutation of both O2- . and free radicals of the drug generating, respectively, H2O2 and 9-oxo-E. 9-Oxo-E further reacts with the 9-OH-E remaining in the solution to form the dimer 9-OH-E2 as the terminal product. The autoxidation process is strongly enhanced by superoxide dismutase and manganese ions. In the ellipticine series, all drugs that have an OH group in position 9 exhibit the ability to transfer one electron on molecular oxygen to generate O2- .. This property may be involved in the cytotoxic activities of these drugs.

Alkaloids↗
PubMed1983

Heterocyclic Quinones. 4. A new highly cytotoxic drug: 6,7-bis(1-aziridinyl)-5,8-quinazolinedione.

With the aim of obtaining new antitumoral agents, a series of 5,8-quinazolinediones was prepared. 5-Amino-6-methoxyquinazoline was oxidized by Fremy's salt to give 6-methoxy-5,8-quinazolinedione. Nucleophilic substitution reaction at C6, electrophilic substitution at C7, and synthesis of 7-amino-6-methoxy-5,8-quinazolinedione, the parent compound of streptonigrin, were studied. These compounds were tested for cytotoxic properties on L1210 leukemia cells in vitro. One of them, 6,7-bis(1-aziridinyl)-5,8-quinazolinedione, which exhibits a high cytotoxic activity (ID50 = 0.08 microM), was further screened in standard antitumor systems, including L1210 leukemia, P388 lymphocytic leukemia, sarcoma 180, and B16 melanocarcinoma. This drug gives a significant antitumoral effect on P388 leukemia but is inactive on other experimental models. Moreover, this compound was found to be highly mutagenic for Salmonella typhimurium TA98 and TA100 strains (Ames test), suggesting that DNA damage could be responsible for its cytotoxicity.

Animals↗
PubMed1983

Control of UV induction of recA protein.

The basal level of recA protein in Escherichia coli K-12 was estimated by an immunoradiometric assay; it is approximately equal to 1,200 molecules per wild-type bacteria in midexponential phase of growth, slightly more in an excision-deficient (uvrA) strain, and markedly more in recF mutants. Kinetics of induction after UV irradiation showed a rapid increase of recA protein content, which reached a peak level after 60-90 min (20- to 55-fold amplification) and then decreased by dilution of the protein in the growing population. In order to obtain an identical extent of induction of recA protein, a 10-fold higher UV dose was necessary in a wild-type strain compared to the uvrA mutant strain. In the uvrA strain, the presence of one or only very few pyrimidine dimers on DNA was accompanied by a measurable increase of the constitutive level of recA protein; however, the unexcised dimers were unable to permanently induce the formation of recA protein. The derepressed promoter of recA gene is one of the strongest in E. coli. Its sequence displays many similarities with that of the strongest early promoters of T5 phage. Mutants (umuC uvrB and recF uvrB) unable to carry out W-reactivation produced high levels of recA protein after UV irradiation. The data suggested that the recF and umuC genes negatively control the regulation of recA protein level.

Bacterial Proteins↗
PubMed1983

Metabolism of the anti-tumour drugs N2-methyl-9-hydroxyellipticinium acetate (NSC 264137) and N2-methyl-9-hydroxyolivacinium acetate in the rat: preliminary identification of biliary 9-(O)-glucuronide and 10-(S)-glutathione conjugates.

The metabolites of the two anti-tumour drugs, N2-methyl-9-hydroxyellipticinium acetate (9-OH-NME, NSC 264137) and N2-methyl-9-hydroxyolivacinium acetate (9-OH-NMO), in bile of i.v.-treated rats have been studied. Three products have been identified in the bile: the unmetabolized drug (17% excreted products for ellipticinium, 3% for olivacinium derivative); a major metabolite, the corresponding 9-(O)-glucuronide (80 and 96%, respectively) and a minor metabolite, a possible 10-(S)-glutathione conjugate (3 and 1%). The elimination yield of these three products excreted over a period of 12 h represents 36% (ellipticinium) and 74% (olivacinium) of the administered dose. The detection of glucuronide and glutathione conjugates of these pyridinium derivatives was possible by direct injection of bile on to h.p.l.c. without prior extraction with organic solvents, in which these polar metabolites are poorly soluble. Metabolites were tentatively identified by the comparison of h.p.l.c. behaviour (retention times and u.v. absorption ratios) with those of reference samples. Reference conjugates have been prepared by chemical synthesis for the 9-(O)-glucuronides and by biosynthesis for the 10(S)-glutathione derivatives. The detection of the GSH conjugates in bile can be considered as the first experimental evidence of the involvement of oxidative activation in vivo of these ellipticine and olivacine derivatives.

Alkaloids↗
PubMed1983

Mutagenicity and cytotoxicity of five antitumor ellipticines in mammalian cells and their structure-activity relationships in Salmonella.

The mutagenicity and cytotoxicity of five antitumor compounds (ellipticines) were investigated in the Chinese hamster ovary cell hypoxanthine-guanine phosphoribosyltransferase assay and in six strains of Salmonella. All five compounds (ellipticine, 9-methoxyellipticine, 9-hydroxyellipticine, 9-aminoellipticine, and 2-methyl-9-hydroxyellipticinium) were cytotoxic and mutagenic in the Chinese hamster ovary cell hypoxanthine-guanine phosphoribosyltransferase assay in the presence or absence of Aroclor 1254-induced rat liver S9, and all except the last compound were mutagenic in Salmonella. Based on the reversion pattern obtained in various frame-shift and DNA repair-proficient (uvrB+) or -deficient (uvrB) strains of Salmonella in the presence or absence of S9, the first three compounds appear to cause frame-shift mutations by both intercalation and covalent bonding with DNA; thus, these are classified as reactive intercalators. However, 9-aminoellipticine intercalates only weakly and may instead exert its mutagenic activity primarily (or exclusively) by forming a covalent adduct with DNA. Compared to the published antitumor data obtained in mice, the results in Salmonella and Chinese hamster ovary cells suggest that the ability of ellipticine, 9-methoxyellipticine, and 9-hydroxyellipticine to intercalate with DNA, induce frame-shift mutations, and cause cell killing is associated with and may be the basis for their antitumor activity. The observation that the ellipticines are mutagenic in mammalian cells suggests that these antitumor agents may be carcinogenic.

Alkaloids↗
PubMed1982

Mitochondrial and nuclear mutagenicity of ellipticine and derivatives in the yeast Saccharomyces cerevisiae.

Haploid strains of the yeast Saccharomyces cerevisiae were tested for their sensitivity to ellipticine and nine derivatives; some of them exhibiting antitumor properties. Different mutagenic properties of ellipticines are described. Charged ellipticines, which were ineffective in Ames' bacterial assay, were found to be potent inducers of the mitochondrial p- mutation: induction proceeded even in the absence of growth. Uncharged ellipticines increased mitochondrial antibiotic resistance mutations, whereas charged derivatives decreased them. Ellipticine derivatives enhanced, reduced, or did not change the reversion frequencies of nuclear auxotrophic markers. The result depended on the strain being tested: no structure-effect relationship existed. As some ellipticine derivatives were mutagenic in Saccharomyces cerevisiae despite being ineffective in Ames' assay, multiple tests should be used to check that chemotherapeutic drugs are devoid of mutagenic properties.

Alkaloids↗
PubMed1982

An immunoradiometric quantitative assay of Escherichia coli recA protein.

A two-site immunoradiometric assay of Escherichia coli recA protein is described ; its sensitivity allows the detection of 0.1 ng of recA protein ; it yields a linear response for amounts of recA protein in the 0.1-7 ng range. It can be directly applied to extracts of Escherichia coli obtained by sonication. Salmonella typhimurium extracts contain some cross-reacting material which share common antigenic determinants with Escherichia coli recA protein but differ from it.

Antigen-Antibody Reactions↗
PubMed1981

[N-Methyl-9 hydroxy-ellipticine (NSC 264-137) in the treatment of malignant metastases. Preliminary results (author's transl)].

In a phase II trial 2 N-Methyl-9-Hydroxy-Ellipticine (NMHE) was administered in weekly infusions of 100mg/m2 over 1 hour to patients with malignant metastases. Prior to injection, the drug was dissolved in 250 ml isotonic glucose. The results were evaluated in 67 patients. Objective regression was observed in 23 (34%) and was superior to 50% in 10 cases. Patients showing signs of regression under treatment were mostly those with breast cancer (10/24 cases), soft tissue sarcoma (3/9 cases) and renal cancer (2/8 cases). The main toxic effect was haemolysis (2 cases), probably due to an immunoallergic mechanism. Attention is drawn to the lack of bone marrow toxicity.

Alkaloids↗
PubMed1981

Bioactivation of the antitumor drugs 9-hydroxyellipticine and derivatives by a peroxidase-hydrogen peroxide system.

Hydroxylation in position 9 (see Table I) of various antitumor drugs derived from ellipticine results, in most cases, in the possible further oxidation of the hydroxylated drugs into free radicals and quinone products in the presence of a peroxidase-H2O2 system. Except for the N6-methyl derivative, free radicals of hydroxyellipticines do not react with neighboring molecules. However, quinone products have been found to be strong electrophilic molecules. They can oxidize NADH into NAD+ through a nonenzymatic process, and, moreover, quinone from N2-methyl-9-hydroxyellipticine may undergo a nucleophilic attack, resulting in an irreversible binding of the drug to bovine serum albumin. Among the drugs tested, those which can be oxidized by peroxidase-H2O2 exhibit the most cytotoxic effect of L1210 cells in vitro.

Alkaloids↗
PubMed1981

Influence of inducers of monooxygenases on cytotoxic efficiency of ellipticine on leukemia L1210 cells.

The effects of some inducers of microsomal cytochrome P450-dependent monooxygenases on the metabolic bioactivation and the cytotoxicity of the antitumoral drug ellipticine (ELPT) were studied. Rate of growth of leukemia L1210 cells was measured in vitro in the absence and presence of ELPT or measured when the ELPT was metabolically transformed by noninbred Sprague-Dawley rat liver microsomes. The animals used were either untreated or pretreated by various inducers such as phenobarbital, 3-methylcholanthrene, beta-naphthoflavone, 2,3,7,8-tetrachlorodibenzo-p-dioxin, Aroclor 1254, or ELPT. The transformation of ELPT into its two main metabolites, 9-hydroxyellipticine (9-OHE) and 7-hydroxyellipticine, was studied and measured by high-pressure liquid chromatography in conjunction with the determination of cytotoxic activity. A large variability was observed in the bioactivation and cytotoxic efficiency of ELPT mediated by the different microsomal preparations: The more P448 and/or P1-450 forms of cytochrome were induced, the more the 9-OHE was produced and the more the cytotoxicity toward L1210 cells was enhanced. These features were compared with those elicited by the activation of cyclophosphamide, which was transformed into cytotoxic metabolites by the cytochrome P450 form specifically induced by phenobarbital-type inducers.

Alkaloids↗
PubMed1981

Ellipticine, 9-hydroxyellipticine, and 9-hydroxyellipiticinum: some biochemical properties of possible pharmacologic significance.

Ellipticine, 5,11-dimethyl-(6H)-pyrido-(4,3,b)-carbazole (NSC 71795) is a potent cytotoxic and antitumor agent. Several of its derivatives share these properties and nine hydroxylated compounds are even more potent. 2-Methyl-9-hydorxyellipticinium (NSC 264-137) has thus recently been shown to display some therapeutic effectiveness in human breast cancers. The biochemical mechanism of this action is discussed in this paper. DNA has been implied as the target of ellipticine and some derivatives; however, these drugs do not break DNA in cultured L1210 cells. Moreover, several other biochemical constituents are able to bind these compounds in vitro as efficiently as DNA. In this paper the interactions between ellipticine and some of those derivatives and (a) ascitic phospholipids monolayers and (b) cytochrome P450 microsomal proteins are studied and discussed. Finally, the hypothesis that the nonhydroxylated ellipticine derivatives might be better cytotoxic agents because they can be oxidized and generate free radical species through a monovalent electron transfer process is presented. This hypothesis is supported by experiments carried out on the oxidation of 9-hydroxyellipticine and 2-methyl-9-hydroxyellipticine by peroxidases.

Alkaloids↗
PubMed1980

Antitumor activity, pharmacology, and toxicity of ellipticines, ellipticinium, and 9-hydroxy derivatives: preliminary clinical trials of 2-methyl-9-hydroxy ellipticinium (NSC 264-137).

Ellipticine and some derivatives are highly cytotoxic substances which kill L1210 cells at concentrations ranging form 10(-8) to 10(-6)M. Some compounds in this series bind with high affinity to DNA (affinity constant between 10(7) M-1 and 10(5) M-1) by intercalation between base pairs. The antitumoral properties of these derivatives are thought to be related to their DNA-binding ability. Both 9-hydroxylation of ellipticine and quaternarization of 2-pyridinic nitrogen tend to increase DNA binding and antitumor activity. 2-Methyl-9-hydroxyellipticine (NSC 264-137) was selected for a phase I and later for a phase II trial in human cancer. This drug does not affect blood cell counts in animals or in man. It is not mutagenic in the Ames' test nor teratogenic in mice, but is endowed with anti-inflammatory properties and induces a marked decrease of motoricity in mice. Transient bradycardia and decrease of blood pressure are the most noticeable cardiovascular effects in dogs. This compound administered at 80-100 mg/m2/week in 1-h intravenous (IV) infusion induces objective remissions in about 25% of patients suffering from advanced breast cancer refractory to all other treatment. These remissions, which occurred after 3-4 weeks, lasted for 1-18 months. This drug seems particularly to improve the condition of patients suffering from oesteolytic breast cancer metastasis. Activity against anaplastic thyroid carcinoma and ovarian carcinoma has also been observed in some cases. Toxic side effects are nausea and vomiting (one-third of the patients), hypertension (less than 10% of the patients), muscular cramp (one-third of the patients), fatigue which can be very pronounced (in most patients after 3 months of treatment), mouth dryness, and mycosis of the tongue and esophagus (less than 20% of the patients).

Alkaloids↗