9cUAB30, an RXR specific retinoid, and/or tamoxifen in the prevention of methylnitrosourea-induced mammary cancers.
Studies were performed in female Sprague-Dawley rats to determine the efficacy of a new RXR specific retinoid (9cUAB30) when combined with tamoxifen in the prevention of mammary cancers and to determine various pharmacokinetic parameters of the retinoid. When administered by gavage, 9cUAB30 was rapidly absorbed and had a serum t(1/2) of 13.5 h. Since the retinoid was administered in the diet for the chemoprevention study, a 28-day study in which 9cUAB30 was given at dose levels of 200, 400, and 600 mg/kg diet revealed fairly constant serum levels regardless of dose or length of treatment; possibly accounting for the observed low toxicity of this compound. When suboptimal doses of 9cUAB30 were given in the methylnitrosourea (MNU)-induced mammary cancer model, the following average number of mammary cancers were observed: 9cUAB30 (150 mg/kg diet), 4.3; tamoxifen (0.4 mg/kg diet), 4.6; 9cUAB30 (150 mg/kg diet)+tamoxifen (0.4 mg/kg diet), 2.6; and controls, 6.0. Thus, the combination of the agents resulted in an increased effect in preventing mammary cancers; suggesting that cancer cell proliferation was inhibited by the compounds blocking different pathways.
Department of Surgery, The University of Alabama at Birmingham, Birmingham, AL 35294, USA. clinton.grubbs@ccc.uab.edu
Clinton J
CJ
Grubbs
Donald L
DL
Hill
Kirby I
KI
Bland
Samuel W
SW
Beenken
Tsu-Han
TH
Lin
Isao
I
Eto
Venkatram R
VR
Atigadda
Kimberly K
KK
Vines
Wayne J
WJ
Brouillette
Donald D
DD
Muccio
D000284:Administration, Oral; D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004032:Diet; D004305:Dose-Response Relationship, Drug; D005231:Fatty Acids, Unsaturated / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control*; D008770:Methylnitrosourea / Q000633:toxicity; D009281:Naphthalenes / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D012176:Retinoids / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology*; D014157:Transcription Factors
D000477:Alkylating Agents; D018931:Antineoplastic Agents, Hormonal; D005231:Fatty Acids, Unsaturated; D009281:Naphthalenes; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D012176:Retinoids; D014157:Transcription Factors; D013629:Tamoxifen; D008770:Methylnitrosourea; C112106:UAB 30