ABSTRACT
Female rats bearing DMBA induced mammary carcinomas were treated with a new anthraquinone derivative related to mitoxantrone. The drug was administered at a dose of 5 mg/kg daily for 10 days. Tumor regression was noted in 78% of the animals with growth rate reduced from +74.91% to -12.60%. The results demonstrate that replacement of a polar hydroxy group of mitoxantrone with a nonpolar hydrocarbon moiety does not impair its antitumor activity and in fact may influence its availability to endocrine systems.
Subject(s)
Antineoplastic Agents/therapeutic use , Mammary Neoplasms, Experimental/drug therapy , Mitoxantrone/analogs & derivatives , Animals , Female , Rats , Rats, Inbred Strains , Structure-Activity RelationshipABSTRACT
The compound 8,11-bis[[2-[(2-hydroxyethyl)amino]ethyl]amino]- 6-methoxy-1,2,3,4-tetrahydro-7,12-benz[a]-anthraquinone (7) was synthesized from 3,6-dimethoxyphthalic anhydride and 6-methoxy-1,2,3,4-tetrahydronaphthalene by a Friedel-Crafts reaction, cyclization to form a dihydroxyanthraquinone, and conversion into the amino-substituted derivative by reaction with 2-[(2-hydroxyethyl)amino]ethylamine. The new compound, a ring D analogue of mitoxantrone, showed growth inhibition, at micromolar concentrations, of murine leukemia 1210, human lung H125, human breast MCF7, human ovary 121, and human colon WiDr and increased the life span of leukemic mice by 38%.
Subject(s)
Anthraquinones/pharmacology , Antineoplastic Agents/chemical synthesis , Ethanolamines/pharmacology , Animals , Anthraquinones/chemical synthesis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Chemical Phenomena , Chemistry , Ethanolamines/chemical synthesis , Humans , Leukemia L1210/drug therapy , Mice , Mice, Inbred DBA , Mitoxantrone , Structure-Activity Relationship , Tumor Cells, Cultured/drug effectsSubject(s)
Mammary Glands, Animal/analysis , Prostaglandins/analysis , Animals , Chromatography, Liquid , Dinoprost , Dinoprostone , Epithelial Cells , Epithelium/analysis , Female , Fibroblasts/analysis , Mammary Glands, Animal/cytology , Mammary Neoplasms, Experimental/analysis , Prostaglandin D2 , Prostaglandins D/analysis , Prostaglandins E/analysis , Prostaglandins F/analysis , Rats , Rats, Inbred StrainsABSTRACT
The compound 7,12-dimethylbenz[a]anthracene (DMBA), a powerful chemical carcinogen, undergoes enzymatic oxidation to a variety of metabolites. Phenols, the monohydroxylated derivatives of DMBA, are an electrophilic species capable of binding covalently with DNA. Although phenols may play a role in carcinogenesis, little information is available regarding these metabolites, many of which are chemically unstable and elusive to quantitative analysis. In this study, a method is described for the methylation of phenolic products to their chemically stable methyl ether derivatives. Application of this procedure to in vitro incubations of DMBA with rat liver microsomes resulted in the isolation and identification of 4-hydroxy DMBA, 8-hydroxy DMBA and 3-hydroxy DMBA.
Subject(s)
9,10-Dimethyl-1,2-benzanthracene/analysis , Phenols/analysis , 9,10-Dimethyl-1,2-benzanthracene/metabolism , Animals , Biotransformation , Chromatography, Liquid , In Vitro Techniques , Membrane Lipids/metabolism , Methylation , Microsomes, Liver/metabolism , Rats , Rats, Inbred Strains , Sodium HydroxideABSTRACT
The antiestrogenic potency of benz[a]anthracene-3,9-diol, as well as its 7- and 12-methyl derivatives, was evaluated by measuring he inhibition in the onset of estrus brought about by this compound in ovariectomized rats treated with 17beta-estradiol. At a dose of 0.5 mg and 7,12-dimethyl derivative caused a decrease in the percentage of rats in estrus from 78 to 44%. This decrease is identical with that caused by 0.05 mg of nafoxidine.
Subject(s)
Benz(a)Anthracenes/chemical synthesis , Estrogen Antagonists/chemical synthesis , Animals , Benz(a)Anthracenes/pharmacology , Chemical Phenomena , Chemistry , Female , Kinetics , Rats , Rats, Inbred StrainsABSTRACT
The daily excretion of estrone, estradiol, and estriol was determined for 22 normal women and 35 women with primary breast cancer. The excretion of the hormones (measured in microgram/24 hr) in the breast cancer group was elevated and showed a statistical significance of P less than 0.001. The same wide difference between the 2 groups was also noted when excretion was expressed in terms of the body area of the individuals and when women of similar ages were compared.
Subject(s)
Breast Neoplasms/urine , Estradiol/urine , Estriol/urine , Estrone/urine , Aged , Breast Neoplasms/diagnosis , Breast Neoplasms/etiology , Female , Humans , Menopause , Middle Aged , RiskABSTRACT
Previously, the 3,9-dihydroxy derivative of benz[a]-anthracene was shown to be weakly estrogenic. The availability of the related diol of the mammary carcinogen dimethylbenz[a]-anthracene, i.e., 3,9-dihydroxy-7,12-dimethylbenz[a]anthracene (3,9-diOHDMBA), prompted a similar study of its estrogenic properties. The competitive binding studies of 3,9-diOHDMBA with 17beta-estradiol in the uterine cytosol of immature SD rats gave a Ka of 1.7 x 10(8) M-1. 17beta-Estradiol (10(-9) M) binding to the 8S binding protein was inhibited by 3,9-diOHDMBA at concentrations similar to those of nafoxidine HCl (1 x 10(-5) M). Bioassay demonstrated that the diol possesses 1/4,464 the activity of 17beta-estradiol.
Subject(s)
9,10-Dimethyl-1,2-benzanthracene , Benz(a)Anthracenes , Estrogens , Receptors, Estrogen/metabolism , 9,10-Dimethyl-1,2-benzanthracene/analogs & derivatives , 9,10-Dimethyl-1,2-benzanthracene/metabolism , 9,10-Dimethyl-1,2-benzanthracene/pharmacology , Animals , Benz(a)Anthracenes/analogs & derivatives , Binding, Competitive , Cytosol/metabolism , Estradiol/metabolism , Female , In Vitro Techniques , Rats , Uterus/metabolismABSTRACT
The estrogen receptor binding properties of 3,9-dihydroxybenz[a]anthracene (3,9-diOHBA) were determined in uterine cytosol of immature Sprague-Dawley rats by competitive binding experiments with [3H]estradiol and sucrose density centrifugation. 3,9-DiOHBA inhibited estradiol binding to the 8S binding protein at a concentration (1.2 X 10(-5) M) approximately equal to that of nafoxidine-HCl (3 X 10(-5) M) required to inhibit estradiol-specific binding, and bioassay for estrogenic activity substantiated this finding.
