Disease relevance of LGD 1069

• METHODS: We evaluated thyroid function in 27 patients with cutaneous T-cell lymphoma who were enrolled in trials of high-dose oral bexarotene at one institution [1].
• CONCLUSIONS: Hypothyroidism may develop in patients with cutaneous T-cell lymphoma who are treated with high-dose bexarotene, most likely because the retinoid X receptor-selective ligand suppresses thyrotropin secretion [1].
• In the HepG2 human hepatoblastoma cell line, both at-RA and 9-cis RA as well as the retinoid X receptor (RXR)-specific agonist LGD 1069, but not the RA receptor (RAR) agonist ethyl-p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-l-pro penyl]-benzoic acid (TTNPB), induce apo A-II mRNA levels [2].
• Exposure to 10(-6) to 10(-10) M bexarotene or Panretin for 48 hours was associated with increased expression of both the p55 and p75 subunits of the IL-2R in T-cell leukemias and p75 in B-cell leukemias [3].
• In this phase I/II trial, we combined bexarotene with cisplatin and vinorelbine in the treatment of patients with non-small-cell lung cancer (NSCLC) [4].

High impact information on LGD 1069

• Our results demonstrate that the combination of denileukin diftitox and bexarotene is well tolerated and that even low doses (150 mg/day) of bexarotene are capable of in vivo upregulation of CD25 expression on circulating leukemia cells [5].
• In vitro studies demonstrated that the retinoid X receptor (RXR) retinoid, bexarotene, at biologically relevant concentrations of 10(-6) M to 10(-8) M, upregulated both the p55 and p75 subunits of the IL-2R and enhanced 5- to 10-fold the susceptibility of T-cell leukemia cells to denileukin diftitox [5].
• To determine whether this biomodulatory effect could be recapitulated in vivo, we treated 14 patients with relapsed or refractory cutaneous T-cell lymphoma with escalating doses of bexarotene (75 mg/day-300 mg/day) and denileukin diftitox (18 mcg/kg per day x 3 days every 21 days) in a phase 1 trial [5].
• In addition to tumor multiplicity, proliferation and apoptosis were modulated by bexarotene treatment independently of estrogen signaling [6].
• The rexinoids LG100268 and bexarotene (LG1069, Targretin) were highly efficacious in the prevention of neu-induced mammary carcinomas [6].

Chemical compound and disease context of LGD 1069

• PURPOSE: Bexarotene (Targretin; Ligand Pharmaceuticals, Inc, San Diego, CA) is a retinoid-X-receptor (RXR)-selective retinoid with preclinical antitumor activity in squamous cell cancers [4].
• LGD1069 (Targretin) is a potent RXR-selective retinoic acid agonist with a reduced toxicity profile compared with other nonselective retinoids [7].
• METHODS: A phase I-II open-label randomized clinical study of bexarotene gel, alone and in combination with a low- and a mid-potency steroid, was conducted in 55 patients with chronic severe hand dermatitis at two academic clinics [8].
• This study evaluated the anti-tumor efficacy of combining the RXR agonist, bexarotene, with the PPARgamma agonist, rosiglitazone, in colon cancer [9].
• The principal toxicities of bexarotene include central hypothyroidism, xeroderma and elevation of cholesterol and triglycerides [10].

Biological context of LGD 1069

• Once the maximum-tolerated dose (MTD) of bexarotene was determined, the study entered the phase II portion [4].
• Abrogation of transforming growth factor-alpha/epidermal growth factor receptor autocrine signaling by an RXR-selective retinoid (LGD1069, Targretin) in head and neck cancer cell lines [7].
• Bexarotene inhibited both tumor multiplicity and tumor volume in mice of all three genotypes [11].
• RESULTS: Repeat exposure to paclitaxel alone resulted in development of paclitaxel resistance with cross-resistance to multidrug resistance P-glycoprotein substrates, whereas the bexarotene/paclitaxel combination prevented the development of drug resistance and the cells remained chemosensitive [12].
• We show that the RXR ligand LGD1069 (Targretin), like gemfibrozil, can activate the PPARalpha/RXR signal-transduction pathway, including transactivation of the bifunctional enzyme or acyl-CoA oxidase response elements in a cotransfection assay [13].

Anatomical context of LGD 1069

• Targretin has indicated chemotherapeutic activity against nonsmall-cell lung cancer and chemoprevention in rat mammary gland [14].
• Furthermore, bexarotene inhibited angiogenesis by directly inhibiting human umbilical vein endothelial cell growth and indirectly inhibiting tumour cell-mediated migration of human umbilical vein endothelial cells through Matrigel matrix [15].
• Our growth inhibition results showed that the bexarotene/paclitaxel combination produced a concentration-dependent synergy in NMU-417 tumor cell line [16].
• Although no direct effect of bexarotene on DNA content in the total K10- cells was shown, further studies on subpopulations within the germinative layer such as stem cells and transit amplifying cells might be worthwhile [17].
• MAIN OUTCOME MEASURES: The capacity of bexarotene to induce apoptosis and its effects on T-cell cytokine production from peripheral blood lymphocytes isolated from patients with Sézary syndrome [18].

Associations of LGD 1069 with other chemical compounds

• CONCLUSION: In patients with advanced NSCLC, bexarotene with cisplatin and vinorelbine yielded acceptable phase II response rates (25%) and was associated with better-than-expected survival (14-month median survival time; 61% 1-year, 32% 2-year, and 30% projected 3-year survival rates) [4].
• RESULTS: Combining erlotinib with bexarotene enhanced growth suppression in vitro compared with each single-agent treatment [19].
• For example, isotretinoin, followed by TSEB (for stage I to II disease) or preceded by chemotherapy (for stage II and IV disease) and bexarotene plus PUVA or photopheresis plus IFN, gave overall response rates of 82% and 69% in patients who had MF and SS, respectively [20].
• In January 2000, Alfa Wassermann signed an agreement with Ligand to exclusively market and distribute Targretin gel and capsules in Italy [21].
• These observations suggest that bexarotene probably has two fundamental effects on thyroid function: to suppress TSH production and to increase thyroid hormone metabolic clearance [22].

Gene context of LGD 1069

• Modulation of IL-2R expression was observed at or above a bexarotene dose of 150 mg/day [5].
• It was hypothesized that combining bexarotene with the EGFR inhibitor, erlotinib, would augment clinical activity [19].
• In this study, we have investigated the ability of bexarotene to inhibit lung tumor progression in the mutant A/J mouse models with genetic alterations in p53 or K-ras, two of the most commonly altered genes in human lung tumorigenesis [11].
• In vivo angiogenesis assay utilising gelfoam sponges, bexarotene reduced angiogenesis in sponges containing vascular endothelial growth factor, epidermal growth factor and basic fibroblast growth factor to various extent [15].
• The rexinoid, bexarotene, represses cyclin D1 and EGFR expression in vitro [19].

Analytical, diagnostic and therapeutic context of LGD 1069

• The degree of suppression of thyrotropin secretion tended to be greater in patients treated with higher doses of bexarotene (>300 mg per square meter of body-surface area per day) and in those with a history of treatment with interferon alfa [1].
• CONCLUSION: Bexarotene can be safely added to platinum-based chemotherapy provided that there is aggressive prophylaxis of hypertriglyceridemia [23].
• Chemoprevention of mammary carcinoma by LGD1069 (Targretin): an RXR-selective ligand [24].
• Identification of biomarkers modulated by the rexinoid LGD1069 (bexarotene) in human breast cells using oligonucleotide arrays [25].
• In vivo, the bexarotene/paclitaxel combination regimen produced a statistically significant decrease in tumor growth in a Calu3 NSCLC xenograft model compared with the single agents (two-tailed, P < 0.05) [12].

References