Efficacy of new retinoids in the prevention of mammary cancers and correlations with short-term biomarkers

Abstract

A number of retinoid X receptor (RXR) agonists have proven to be highly effective in preventing methylnitrosourea (MNU) induced mammary cancers. However, these agonists have side effects; particularly causing an increase in serum triglyceride levels. A series of ligands for RXR were designed based on computer modeling to the ligand binding domain (LBD) of the RXR receptors and on structure-activity relationships. The chemopreventive effects of these retinoids were evaluated in the relatively long-term MNU model. As a short-term assay to predict their efficacy, the ability of the retinoids to modulate cell proliferation and apoptosis was also determined in mammary cancers after only 7 days of treatment. The five UAB retinoids evaluated included two Class I UAB retinoids (UAB20, UAB112) and three Class II UAB retinoids (UAB30, 4-methyl-UAB30 and the benzosuberone-analog of UAB30). The previously evaluated RXR agonist targretin and the pan-agonist 9-cis-retinoic acid (9-cis-RA), which interacts with both RAR and RXR receptors, were included as positive agonists known to prevent cancer in the MNU model. In the prevention studies, in which the agents were administered beginning 5 days after MNU until the end of the study, targretin (150 mg/kg diet) and 4-methyl-UAB30 (200 mg/kg diet) were highly effective in decreasing cancer numbers by 75-85%. UAB30 (200 mg/kg diet) and 9-cis-RA (60 mg/kg diet) gave intermediate inhibitions of 60 and 45%, respectively. Targretin (15 mg/kg diet), UAB20 (200 mg/kg diet) and the benzosuberone analog of UAB30 (200 mg/kg diet) showed limited activity by decreasing cancer multiplicity 25-30%, while UAB112 had no effect on mammary cancer multiplicity. A direct correlation was observed between the long-term chemopreventive efficacy of these agents and their ability to decrease cell proliferation in mammary cancers after short-term treatment. Furthermore, the highly effective agents (4-methyl-UAB30 and targretin at 150 mg/kg diet) increased apoptosis 3-5 times, while agents with moderate or limited preventive efficacy failed to significantly increase apoptosis. Although the more effective retinoid treatments increased serum triglycerides 2.5- to 4.0-fold, one moderately effective agent (UAB30) had no significant effect on lipid levels. In summary, a short-term in vivo method has been identified for screening newly synthesized retinoids both for chemopreventive efficacy and for their adverse effect on serum triglycerides.

Aerosolized Bexarotene Inhibits Lung Tumorigenesis without Increasing Plasma Triglyceride and Cholesterol Levels in Mice

“…Its effectiveness by oral delivery was further demonstrated by our group where oral gavage of 180 mg/kg bexarotene significantly decreased small cell lung carcinoma incidence in a lungspecific Rb1 and p53 knockout model (23). However, and similar to the human situation, bexarotene delivered orally causes hypertriglyceridemia in rodents as well (24). Mice treated with 30 mg/kg bexarotene by oral gavage, a dose that shows minor efficacy in vinyl carbamate-induced mouse lung tumors, does increase plasma TG levels 2-fold (25).…”

Defining the Communication between Agonist and Coactivator Binding in the Retinoid X Receptor α Ligand Binding Domain

“…We have demonstrated that 9cUAB30 compared well with Targretin in its capacity to prevent mammary cancer (21)(22)(23)(24)(25). The in vitro studies presented here also show how similar each rexinoid is in blocking ErbB2-oncogenic transformation, consistent with in vivo studies.…”

“…Although 9cUAB30 is slightly less potent than Targretin or 9cRA, it displays a higher degree of RXR selectivity. 9cUAB30 has also been shown to be effective in cancer prevention models (21)(22)(23)(24)(25). 9cUAB30 is a tissue-selective RXR agonist; it does not act as an agonist in liver to activate lipid biosynthesis although it has agonist capabilities in cancer cells (26).…”

Effects of gefitinib (Iressa) on mammary cancers: preventive studies with varied dosages, combinations with vorozole or targretin, and biomarker changes

“…One group of end points is the effects of short-term exposure to agents on proliferation and apoptosis in small palpable mammary cancers. These end points have been used in examining a wide variety of agents, including aromatase inhibitors, selective ER modulators, and farnesyltransferase inhibitors (18), as well as in screening a variety of RXR agonists for chemopreventive activity (19). An excellent correlation was found between decreases in proliferation and increases in apoptosis and long-term chemopreventive and therapeutic efficacies.…”