Biomedical subjects

E J Lavoie

Publications and source records attributed to E J Lavoie.

14 recordsLinked to original sources

PubMed2000

Topoisomerase I inhibition and cytotoxicity of 5-bromo- and 5-phenylterbenzimidazoles.

Topoisomerase I is an enzyme that is essential for maintaining the three-dimensional structure of DNA during the processes of transcription, translation and mitosis. With the introduction of new clinical agents that are effective in poisoning topoisomerase I, this enzyme has proved to be an attractive molecular target in the development of anticancer drugs. Several terbenzimidazoles have been identified as potent topoisomerase I poisons. Structure-activity data on various terbenzimidazoles have revealed that the presence of lipophilic substituents at the 5-position of various terbenzimidazoles correlates with enhanced cytotoxicity. While the effect of having substituents at both the 5- and 6-positions had not been evaluated, previous studies did indicate that the presence of a fused benzo-ring at the 5,6-position results in a significant decrease in topoisomerase I poisoning activity and cytotoxicity. In the present study we investigated whether substituents at both the 5- and 6-positions of varied terbenzimidazoles would allow for retention of topo I poisoning activity. The 6-bromo, 6-methoxy, or 6-phenyl derivatives of both 5-bromo- and 5-phenylterbenzimidazole were synthesized and evaluated for topo I poisoning activity, as well as their cytotoxicity toward human lymphoblastoma cells. The data indicate that such derivatives do retain similar topo I poisoning activity and possess cytotoxicity equivalent to either 5-bromo- or 5-phenylterbenzimidazole. Significant enhancement in the topoisomerase I poisoning activity and cytotoxicity of 5-phenylterbenzimidazole is observed when the 2"-position is substituted with either a chloro or trifluoromethyl substituent. The influence of such substituents on the biological activity of 5.6-dibromoterbenzimidazole (6a) was also explored. In the case of either 2"-chloro-5,6-dibromoterbenzimidazole (6b) or 2"-trifluoromethyl-5,6-dibromoterbenzimidazole (6c), topoisomerase I poisoning was not enhanced relative to 6a. While cytotoxicity toward RPMI 8402 was also not significantly affected, comparative studies performed against several solid human tumor cell lines did reveal a significant increase in cytotoxicity observed for 6c as compared to 6a.

Benzimidazoles↗

PubMed1996

Characterizing the DNA binding modes of a topoisomerase I-poisoning terbenzimidazole: evidence for both intercalative and minor groove binding properties.

We have used a broad range of spectroscopic and viscometric techniques to demonstrate that the complexation of a cytotoxic, topoisomerase I-poisoning terbenzimidazole (5PTB) with the poly(dA).poly(dT) duplex exhibits properties characteristic of both intercalation and minor groove binding. Our results reveal the following features: (i) Optical melting profiles reveal that 5PTB binding enhances the thermal stability of the poly(dA).poly(dT) duplex; (ii) Fluorescence-detected 5PTB binding to the poly(dA).poly(dT) duplex reveals four apparent "site sizes," ranging from 1 to 13 base pairs (bp) per bound drug; (iii) Flow linear dichroism data suggest conformational heterogeneity among the poly(dA).poly(dT)-bound 5PTB molecules, with substantial contributions from drug molecules bound in the minor groove; (iv) Fluorescence resonance energy transfer data reveal properties characteristic of a significant contribution from an intercalative mode of binding; (v) Viscometric, fluorescence quenching, and netropsin competition data are consistent with 5PTB binding to poly(dA).poly(dT) by "mixed" modes, which are operationally defined as single or multiple binding populations that individually and/or collectively express both intercalative and minor groove binding properties. We comment on a potential correlation between drugs that exhibit such "mixed" mode binding motifs and those that express antineoplastic activity through inhibition of topoisomerase I.

Benzimidazoles↗

PubMed1994

Prodrugs of hydroxymethylpentamethylmelamine: a principal active metabolite of the antineoplastic agent hexamethylmelamine.

Hexamethylmelamine is in clinical use as an antineoplastic agent. Derivatives and prodrugs of two of its biologically-active metabolites were prepared in an effort to alter its solubility and to enhance bioavailability. In this study prodrugs of pentamethylmelamine and hydroxymethylpentamethylmelamine were synthesized. Among the compounds prepared were N-(methoxymethyl)pentamethylmelamine, N-(ethylthiomethyl)pentamethylmelamine, and several N'-alkyl-N'-methyl-N-(aminomethyl)pentamethylmelamine and N'-aryl-N'-methyl-N-(aminomethyl)pentamethylmelamine derivatives. The aqueous solubility of these prodrugs relative to hexamethylmelamine was compared. The half-lives of these prodrugs were also determined at pH 7.4. The more stable derivatives were assayed at pH 6.4. These prodrugs represent a novel approach for the delivery of the suspect active metabolite of hexamethylmelamine, hydroxymethylpentamethylmelamine.

Altretamine↗

PubMed1988

The influence of fluoranthene on the metabolism and DNA binding of benzo[a]pyrene in vivo in mouse skin.

The effect of the cocarcinogen fluoranthene on the DNA binding and metabolism of [3H]benzo[a]pyrene (B[a]P) in vivo in mouse skin has been investigated. In the presence of fluoranthene the level of B[a]]P-DNA binding was increased at each of the time intervals examined (4, 8, 24 and 48 h) with enhancements ranging from 76% at 4 h to 36% at 48 h. The ratio of anti-7,8,-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (anti-BPDE)-DNA adducts/syn-BPDE-DNA adducts was also increased in the presence of fluoranthene. This increase was greatest at 8 h (44%) but by 48 h the ratio was identical in the presence and absence of fluoranthene. The observed increase in anti-BPDE-DNA adducts/syn-BPDE-DNA adducts did not parallel increases in B[a]P-DNA binding suggesting that alteration of the anti-BPDE/syn-BPDE ratio is not a major contributing factor to the cocarcinogenic activity of fluoranthene. The influence of fluoranthene on the metabolism of B[a]P in vivo in mouse skin was also investigated. Fluoranthene was found to have little or no effect on the formation of ethyl acetate extractable metabolites of B[a]P in mouse skin. Specifically, there was no increase in the amount of B[a]P-7,8-diol in the presence of fluoranthene. Fluoranthene also had little or no effect on the levels of beta-glucuronide or sulfate conjugates of B[a]P metabolites formed in vivo in mouse skin. These studies suggest that the effect of fluoranthene is being expressed at some point after B[a]P has been activated to an ultimate carcinogen.

Animals↗

PubMed1987

Identification of metabolites of benzo[j]fluoranthene formed in vitro in rat liver homogenate.

The metabolites of benzo[j]fluoranthene (BjF) as formed in vitro using the 9000 X g supernatant from Aroclor-pretreated rats have been identified. Two dihydrodiols, trans-4,5-dihydro-4,5-dihydroxyBjF and trans-9,10-dihydro-9,10-dihydroxyBjF have been identified as major metabolites by comparison of their spectral and chromatographic properties with those of pure synthetic standards. There was no evidence that any of the isomeric 2,3-dihydrodiol was formed as a metabolite of BjF under these incubation conditions. Neither of the metabolic dihydrodiols of BjF were formed with a high degree of stereoselectivity. The enantiomeric purity of the 4,5-dihydrodiol was 20% while that of the 9,10-dihydrodiol was 46%. At least four phenols were detected among the metabolites of BjF. These were identified as 3-, 4-, 6- and 10-hydroxyBjF based upon comparison of their UV spectra and HPLC retention times with those of synthetic reference standards. BjF-4,5-dione was also identified as a metabolite under these incubation conditions.

Animals↗

PubMed1987

Tumorigenic activity of non-alternant polynuclear aromatic hydrocarbons in newborn mice.

The tumorigenic activity of benzo[b]fluoranthene, benzo[j]fluoranthene, benzo[k]fluoranthene, and indeno-[1,2,3-cd]pyrene was evaluated in newborn CD-1 mice. The total doses of these non-alternant polycyclic aromatic hydrocarbons employed in this study ranged from 0.5 to 2.1 mumol per mouse. The results of this assay indicate that both benzo[b]fluoranthene and benzo[j]fluoranthene exhibit significant tumorigenic activity. In contrast to these results, neither benzo[k]fluoranthene nor indeno[1,2,3-cd]pyrene were tumorigenic under these assay conditions.

Animals↗

PubMed1985

Pharmacokinetics of N'-nitrosonornicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in laboratory animals.

The pharmacokinetics of N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in the Syrian golden hamster, the CD-1 mouse, and the baboon were compared to the pharmacokinetics in the Fischer rat. The formation and biological half-life of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), the major metabolite of NNK, was also studied in these animal species. The biological half-life of NNN in these 4 animal species ranged from 0.24 h to 3.06 h, that of NNK from 0.21 h to 0.43 h and NNAL from 0.48 h to 2.9 h. The pharmacokinetic data obtained in the baboon suggest that treatment with NNN and NNK causes an enzyme induction which accelerates the rate of elimination of these compounds.

Animals↗

PubMed1985

Studies on the mutagenicity and tumor-initiating activity of methylated fluorenes.

Several methylated analogs of fluorene were evaluated as mutagens in Salmonella typhimurium TA98 and TA100 in the presence and absence of microsomal activation. Among the methylated derivatives of fluorene assayed were 9-methylfluorene, 2-fluoro- and 2,7-difluoro-9-methylfluorene, 1,9-, 2,9-, 3,9- and 4,9-dimethylfluorene, 2,3,9-trimethylfluorene and 2,7,9-trimethylfluorene. Mutagenic activity was observed for several of these fluorene derivatives in the presence of rat liver homogenate. The data support a previous observation that a single methyl substituent in the 9-position of fluorene is associated with mutagenic activity within this series of compounds. Substitution with fluorine at both the 2- and 7-positions of 9-methylfluorene was not associated with a loss of mutagenic activity as evidenced by the similar mutagenic activity of 2,7-difluoro-9-methylfluorene and 9-methylfluorene. However, 2,7,9-trimethylfluorene was not mutagenic under these assay conditions. 9-Methylfluorene, 1,9-, 2,9-, 3,9- and 4,9-dimethylfluorene and 2,3,9-trimethylfluorene were active as mutagens in the presence of rat liver homogenate, but were inactive as tumor initiators when assayed on mouse skin.

Animals↗

PubMed1985

Methylene-bridged bay region chrysene and phenanthrene derivatives and their keto-analogs: mutagenicity in Salmonella typhimurium and tumor-initiating activity on mouse skin.

A series of methylene-bridged and keto-bridged bay region derivatives of chrysene and phenanthrene were prepared and evaluated for mutagenic activity in Salmonella typhimurium TA100 and for tumor-initiating activity on CD-1 mouse skin. The compounds included in this series were 4H-cyclopenta[def]phenanthrene, 4H-cyclopenta[def]phenanthrene-4-one, 1-methyl-4H-cyclopenta[def]phenanthrene, 1-methyl-4H-cyclopenta[def] phenanthren-4-one, 4H-cyclopenta[def] chrysene, and 4H-cyclopenta[def] chrysen-4-one. Among these compounds only 4H-cyclopenta[def]phenanthrene and 1-methyl-4H-cyclopenta[def]phenanthren-4-one were not significantly mutagenic when assayed with metabolic activation using Aroclor-induced rat liver homogenate. None of the compounds assayed were active without metabolic activation. 4H-Cyclopenta[def]chrysene was the most tumorigenic of the methylene-bridged bay region PAH tested on mouse skin. At a dose of 1.0 mg this compound resulted in 100% of the animals bearing papillomas with 5.63 papillomas/animal. 4H-Cyclopenta[def]chrysen-4-one and 1-methyl-4H-cyclopenta[def]phenanthrene displayed weak tumorigenic activity at a total initiating dose of 1.0 mg.

Animals↗

PubMed1985

Nicotine: a precursor for carcinogens.

Eric Boyland and collaborator demonstrated about 20 years ago that N'-nitrosonornicotine (NNN), a suspected smoke constituent, was a lung carcinogen in mice and that thiocyanate, a major detoxification product of the smoke component hydrogen cyanide, catalyzes the endogenous formation of nitrosamines. Also, Boyland presumed that the enzymatic conversion of nicotine may contribute to the carcinogenic potential of cigarette smoke via reactive intermediates. Chemical, biochemical and bioassay data gathered since these first observations, support the concept that the nicotine-derived NNN and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) contribute significantly to the carcinogenic activity of snuff and cigarette smoke. Reactive metabolites of nicotine may also be carcinogenic factors. This hypothesis requires exploration.

Animals↗

PubMed1984

Fluoranthene and pyrene enhance benzo[a]pyrene--DNA adduct formation in vivo in mouse skin.

Fluoranthene and pyrene are potent cocarcinogens when applied together with benzo[a]pyrene (BaP) on mouse skin. In this study the effect of fluoranthene, pyrene and phenanthrene on the formation of BaP--DNA adducts in mouse skin was investigated. Co-application of either fluoranthene or pyrene with [3H]BaP resulted in an average increase in the level of [3H]BaP--DNA adducts of 56% to 66%, respectively, as compared to [3H]BaP alone. Only minor differences were observed in the ratio of (+/-)anti- to (+/-)synbenzo[a]pyrene diol epoxide--DNA adducts between experimental groups. An average 17% decrease in the formation of [3H]BaP--DNA adducts was observed upon co-application of [3H]BaP on mouse skin with phenanthrene. These data suggest a correlation between the observed increase in tumorigenicity of BaP in the presence of either fluoranthene or pyrene and an increase in the formation of (+/-)anti-benzo[a]pyrene diol epoxide--DNA adducts.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗

PubMed1984

Pharmacokinetics of tobacco-specific N-nitrosamines.

Methods were developed to determine the biological half-life of N'-nitrosonornicotine (NNN) and 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK) in Syrian golden hamsters and Fischer rats. The formation and elimination of 4-(N-nitrosomethylamino)-1-(-3-pyridyl)-1-butanol (NNA1), the major metabolite of NNK, was determined in the context of this study. The method consisted of extraction of the nitrosamine with ethyl acetate, elution through a Clin-Elut column, and concentration of the sample, followed by gas chromatography-thermal energy analysis. Biological half-lives of NNN, NNK and NNA1 in hamsters were found to be 0.77, 0.25 and 1.78 h, respectively; in rats they were 5.78, 1.78 and 3.56 h. These findings clearly indicate species differences in the pharmacokinetics associated with the distribution and elimination of the tobacco-specific N-nitrosamines.

Animals↗

PubMed1981

The influence of methyl substitution of the mutagenicity of nitronaphthalenes and nitrobiphenyls.

A series of nitrobiphenyls, nitronaphthalenes, and their methyl-substituted derivatives were assayed for mutagenicity toward S. typhimurium TA98 and TA100. In assays conducted in the absence of rat liver S9 fraction, substitution of a methyl group ortho to the nitro group decreased mutagenicity (3-methyl-4-nitrobiphenyl, 2-methyl-1-nitronaphthalene, and 3-methyl-2-nitronaphthalene). The mutagenicity of 4-nitrobiphenyl was also inhibited by methyl substitution at the 2'-position (2'-methyl-4-nitrobiphenyl), and at both the 3- and 2'-positions (3,2'-dimethyl-4-nitrobiphenyl). In assays conducted in the presence of rat liver S9 fraction, inhibition of mutagenicity by methyl substitution was demonstrated for 2-methyl-1-nitronaphthalene, 3-methyl-2-nitronaphthalene and 3,2'-dimethyl-4-nitrobiphenyl. Thus, methyl substitution of nitrobiphenyls and nitronaphthalenes generally decreased mutagenicity, when assays were conducted in the absence of rat liver S9 fraction. However, in the presence of rat liver S9 fraction, the inhibitory effect of methyl substitution on mutagenicity was less pronounced. These results contrast to the usual enhancing effect of ortho-methyl substitution of the corresponding aromatic amines and their N-oxidized derivatives (hydroxylamines and C-nitroso compounds).

Animals↗

PubMed1981

Mutagenicity of methylated fluorenes and benzofluorenes.

Methylated fluorenes were assayed for mutagenic activity towards Salmonella typhimurium TA98 and TA100. None of these methylfluorenes were mutagenic in the absence of metabolic activation. In the presence of 9000 X g supernatant from Aroclor-induced rats, 9-methylfluorene and 1,9-dimethylfluorene were active towards TA98 and TA100. The structural requirement for mutagenic activity within this series was the presence of a single methyl substituent at the 9-position. Enhanced mutagenic activity was also observed for benzofluorenes similarly methylated at their benzylic positions.

Animals↗