Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

LGD1069 [Targretin; 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphtalenyl) propenyl] benzoic acid] is a novel synthetic retinoid X receptor-selective retinoid that has been recently identified. The goals of this study were to determine the safety, toxicity, pharmacokinetics (PKs), and metabolic profile of LGD1069 in advanced cancer patients. Sixty patients received oral LGD1069 at doses ranging from 5-1000 mg/m2/day with PK sampling performed on days 1 and 15. No dose-limiting toxicities (DLTs) were observed up to the 500 mg/m2/day dose level. DLT observed at and above 650 mg/m2/day included skin desquamation, hyperbilirubinemia, transaminase elevation, leukopenia, and diarrhea. Asymptomatic, dose-related alterations in lipid and thyroid metabolism were also observed. DLTs frequently observed with retinoic acid receptor-selective retinoids and pan agonists, including headache, mucocutaneous toxicity, and hypercalcemia, were not dose-limiting with LGD1069. Day 1 LGD1069 Cmax and area under the curve values increased dose-proportionately up to 800 mg/m2/day. Repeat-dose (day 15) area under the curve values varied between 25 and 105% of day 1 values. Although no objective tumor responses were observed, tumor progression may have been substantially arrested or delayed in non-small cell lung cancer (5 of 16) and in head and neck cancer (1 of 5), as well as other tumor types. At the higher dose levels, the molar concentration of LGD1069 was up to 10-fold higher than observed with other retinoids, yet toxicity was minimal. LGD1069 is an retinoid X receptor-selective retinoid agonist with a more favorable PK and toxicity profile than previously studied retinoids and merits further investigation as a chemopreventive and anticancer agent. On the basis of this Phase I trial, the recommended Phase II dose is 500 mg/m2/day.
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PMID:A Phase I study of LGD1069 in adults with advanced cancer. 1043 65

A phase II study was undertaken to determine the efficacy of Bexarotene in melanoma. Between November 1997 and April 1998, 19 patients were given Bexarotene in single daily oral doses of 450 mg/m2 in capsule form continuously. Nineteen patients, four with choroidal metastatic melanoma, were treated. No responses were seen. Five patients had stable disease, two of the four with choroidal melanoma, had tumor progression. Myelosuppression was mild. Grade 3 myalgia, asthenia, diarrhea, cold hands/feet, and mood changes were seen in one patient each. Changes in serum triglyceride and thyroxine levels were common. Bexarotene, as used in this study, is not effective against melanoma.
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PMID:A phase II evaluation of bexarotene (Targretin) capsules in patients with metastatic melanoma. 1085 63

Bexarotene (Targretin), is a synthetic high-affinity RXR receptor agonist with limited affinity for RAR receptors. Bexarotene has shown efficacy in a phase I/II trial of non-small-cell lung cancers. However, the chemopreventive efficacy of bexarotene has not been determined in mouse lung cancer models. 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. Mice were administered vinyl carbamate (VC), a carcinogen, by a single intraperitoneal injection (i.p.) at 6 weeks of age. Bexarotene was given by gavage starting at 16 weeks after VC and was continued for 12 weeks. Although all mice developed lung tumors, only 7% of lung tumors were adenocarcinomas in wild-type mice, whereas 22 and 26% of lung tumors were adenocarcinomas in p53 transgenic or K-ras heterozygous deficient mice. Bexarotene inhibited both tumor multiplicity and tumor volume in mice of all three genotypes. Furthermore, bexarotene reduced the progression of adenoma to adenocarcinoma by approximately 50% in both p53(wt/wt)K-ras(ko/wt) and p53(wt/wt)K-ras(wt/wt) mice. Thus, bexarotene appears to be an effective preventive agent against lung tumor growth and progression.
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PMID:Prevention of lung cancer progression by bexarotene in mouse models. 1624 46