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B Monsarrat

Publications and source records attributed to B Monsarrat.

44 records · Page 3Linked to original sources
PubMed1982

Structures of the adducts formed between [Pt(dien)Cl]Cl and DNA in vitro.

The products of the reaction between [Pt(dien)Cl]Cl and salmon sperm DNA have been purified and their structures determined. [Pt(dien)Cl]Cl binds at the N7 position of guanine for levels of fixation below 0.1 platinum per DNA base. Above this level of binding, [Pt(dien)Cl]Cl also reacts at the N7 position of adenine. 1,7-[Pt(dien)]2Ade was observed when more than 0.3 platinum per base were bound to the DNA. Platination at the N7 position of guanosine, unlike alkylation, stabilized the glycosyl linkage and did not lead to fission of the imidazole ring at high pH.

Animals↗
PubMed1981

Ellipticines and human liver microsomes: spectral interaction with cytochrome P-450 and hydroxylation. Inhibition of aryl hydrocarbon metabolism and mutagenicity.

Some pharmacological properties of ellipticine (E) and its derivatives linked to their interaction with cytochrome P-450 have been investigated with human liver microsomes. 9-Hydroxyellipticine (9-OHE) interacts with human liver cytochrome P-450 exhibiting a type II spectrum (lambda max: 428 nm, Ks = 1.1 microM). After incubation with human liver microsomes the E was converted to 9-OHE; 7-hydroxyellipticine was not produced. The cytotoxic effect of this biotransformation has been evaluated on leukemic L1210 cells, in vitro, and found to be equal to those elicited by liver microsomes of control or phenobarbital (PB) pretreated rats. Moreover, 9-OHE and 9-fluoroellipticine (9-FE) strongly inhibit the benzo[alpha]pyrene hydroxylase (AHH) activity of human liver microsomes (I50 = 2.6 microM and 1.6 microM, respectively) as well as the mutagenesis induced by the polycyclic aromatic hydrocarbon 2-acetylaminofluorene (AAF); 1 microgram/plate of each of these compounds is able to inhibit by more than 50% the mutagenicity of 5 microgram/plate AAF.

2-Acetylaminofluorene↗
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↗
PubMed1980

Mass spectrometry as a technique for testing the purity of drugs for biological use: the case of new antitumor cyclophosphazenes.

Mass spectrometry has been used for testing the chemical purity of some new antitumor cyclophosphazene compounds. the spectrum of N3P3Az6 (code name MYKO 63)--which exhibits noticeable activity on murine P 388, L 1210 and B 16 tumors--appeared to be remarkably simple, as most of the fragmentations arose from successive losses of the aziridino radicals. Traces of the pentaziridinomonochloro impurity formed by an incomplete substitution of N3P3Cl6 chlorine atoms under aziridinolysis could be detected in an impure and toxic sample by spectral subtraction. Quantification of this impurity was performed by selected ion monitoring in the direct inlet mode of sample introduction. The mass spectra of other derivatives of this class of compounds are slightly more complex, since the decomposition pathways showed more intense H-transfers associated with the loss of substituents.

Antineoplastic Agents↗
PubMedDate not supplied

Taxol metabolism. Isolation and identification of three major metabolites of taxol in rat bile.

The elimination of nonradioactive taxol in bile and urine was investigated in the rat after administration via the caudal vein (10 mg/kg). As in humans, no metabolites of taxol were detected by HPLC in rat urine, and only 10% of the injected taxol was recovered in urine over a 24-hr period. In contrast, 11.5% and 29% of the injected taxol was recovered in rat bile as unchanged taxol and metabolites, respectively. Among the nine taxol metabolites detected by HPLC, the side chain at C13, which is required for pharmacological activity, had been removed in only one minor metabolite, baccatin III. The chemical structures of the two major hydroxylated metabolites were determined by mass spectrometry (fast atom bombardment and desorption chemical ionization) and 1H-NMR spectroscopy. One was a taxol derivative hydroxylated on the phenyl group at C3' of the side chain at C13, while the other corresponded to a taxol derivative hydroxylated in the m-position on the benzoate of the side chain at C2. Although these two major taxol metabolites were as active as taxol in preventing cold microtubule disassembly, they were, respectively, 9 and 39 times less cytotoxic as taxol on in vitro L1210 leukemia growth. These results show for the first time that there is a significant hepatic metabolism of taxol.

Alkaloids↗
PubMedDate not supplied

Cytochrome P-450-mediated O-demethylation of two ellipticine derivatives. Differential effect of the murine Ah locus phenotype.

The O-demethylation of two antitumor drugs (9-methoxyellipticine and a 1-polyalkylamino-substituted analog) was studied by incubation with liver microsomes from rats and mice. The former drug underwent a cytochrome P1-450-independent biotransformation in mice, as shown by an indiscriminate response from individuals genetically responsive or nonresponsive to induction by 3-methylcholanthrene. On the other hand, the second drug was O-demethylated only by genetically responsive mice after pretreatment by 3-methylcholanthrene. It was also O-demethylated predominantly in rats pretreated with either 3-methylcholanthrene or Aroclor 1254.

Alkaloids↗
PubMedDate not supplied

Identification of the glucuronide and glutathione conjugates of the antitumor drug N2-methyl-9-hydroxyellipticinium acetate (Celiptium). Comparative disposition of this drug with its olivacinium isomer in rat bile.

Two metabolites of the antitumor drug N-2-methyl-9-hydroxyellipticinium acetate (Celiptium) were isolated from bile of 10 mg/kg iv-treated rats. These metabolites were characterized by UV-visible, mass and proton-NMR data and identified as (i) 9-(O)-glucuronide conjugate and (ii) 10-(S)-glutathione adduct. Evidence for the same type of metabolites for the isomer N-2-methyl-9-hydroxyolivacinium acetate was supported by HPLC data. Despite their minor structural differences (change into a methyl position), the biliary excretion profile of these two drugs is rather different quantitatively: total metabolites excreted within a 12-hr period is 33 +/- 4% of the administered dose for ellipticinium and 70 +/- 6% for olivacinium. The major metabolite is the 9-(O)-glucuronide conjugate for those two drugs: 25 +/- 3% of the dose of ellipticinium and 67 +/- 5% for olivacinium derivative. In both cases, the presence of the 10-(S)-glutathione adduct as a minor metabolite [1.5 +/- 0.5 of the dose (ellipticinium) and 1 +/- 0.5 (olivacinium)] supports the hypothesis that a "biooxidative alkylation" process could occur in vivo.

Alkaloids↗