CGS 16949A, a new nonsteroidal aromatase inhibitor: effects on hormone-dependent and -independent tumors in vivo

CGS 16949A is a very potent and highly selective inhibitor of the aromatase enzyme system in vitro and of estrogen biosynthesis in vivo. These characteristics are reflected in the marked efficacy with which it affects growth of estrogen-dependent 7,12-dimethylbenz(a)antracene-induced mammary carcino...

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Published inCancer research (Chicago, Ill.) Vol. 48; no. 4; pp. 834 - 838
Main Authors SCHIEWECK, K, BHATNAGAR, A. S, MATTER, A
Format Journal Article
LanguageEnglish
Published Philadelphia, PA American Association for Cancer Research 15.02.1988
Subjects
9,10-Dimethyl-1,2-benzanthracene
Aminoglutethimide - therapeutic use
Animals
Antineoplastic agents
Aromatase Inhibitors
Biological and medical sciences
Body Weight - drug effects
Cell Line - drug effects
Chemotherapy
Drug Screening Assays, Antitumor
Fadrozole
Female
Imidazoles - therapeutic use
Mammary Neoplasms, Experimental - drug therapy
Medical sciences
Nitriles - therapeutic use
Pharmacology. Drug treatments
Rats
Tamoxifen - therapeutic use
Antineoplastic agent
Vertebrata
Hormonodependence
Mammalia
Rat
Mouse
Animal
Aromatase
Rodentia
Enzyme inhibitor
Mammary gland
Experimental tumor
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Summary:CGS 16949A is a very potent and highly selective inhibitor of the aromatase enzyme system in vitro and of estrogen biosynthesis in vivo. These characteristics are reflected in the marked efficacy with which it affects growth of estrogen-dependent 7,12-dimethylbenz(a)antracene-induced mammary carcinomas in intact female Sprague-Dawley rats. Daily p.o. treatment of tumor-bearing rats for 42 days with CGS 16949A at doses of 1.0 to 8.0 mg/kg caused almost complete regression of palpable tumors and almost totally suppressed the appearance of new tumors. A dose of about 0.1 mg/kg corresponded to the 50% effective dose, and a fully effective dose was estimated to be about 2.0 mg/kg. Eight to 10 days after cessation of treatment, tumor regrowth was observed. No unexpected side-effects were noted during the course of treatment. Tumors, which were allowed to regrow after a first treatment with CGS 16949A, were similarly efficaciously suppressed with a second treatment with CGS 16949A. Continuous long-term treatment with 2.0 mg/kg for 27 wk caused complete regression of tumors, suppressed the appearance of new tumors completely, and significantly prolonged the survival time of the tumor-bearing rats. This treatment schedule caused no major hematological or blood chemistry changes and was very well tolerated. CGS 16949A was ineffective against transplantable hormone-independent tumors such as R-3230AC mammary carcinoma, 11095 prostate carcinoma, leukemia L1210, and B16 melanoma.
ISSN:0008-5472
1538-7445