Initial Clinical Trial of a High-affinity Retinoic Acid Receptor Ligand (LGD1550)
Retinoids mediate their biological response by binding to specific nuclear receptors, including retinoic acid receptors and/or retinoid X receptors. LGD1550 is a high-affinity ligand for all three retinoic acid receptors (α, β, and γ isoforms) and a potent inhibitor of AP-1, a protein that is closel...
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Veröffentlicht in: | Clinical cancer research 2000-05, Vol.6 (5), p.1731 |
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Sprache: | eng |
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Zusammenfassung: | Retinoids
mediate their biological response by binding to specific nuclear
receptors, including retinoic acid receptors and/or retinoid X
receptors. LGD1550 is a high-affinity ligand for all three retinoic
acid receptors (α, β, and γ isoforms) and a potent inhibitor of
AP-1, a protein that is closely linked with trophic responses and
malignant transformation. We conducted a dose ranging study to evaluate
the pharmacokinetics, safety, clinical tolerance, and potential
efficacy of this drug in patients with advanced cancer. Twenty-seven
patients received oral doses of LGD1550 once per day at doses ranging
from 20–400 μg/m 2 . Skin toxicity was the dose-limiting
reaction at the 400 μg/m 2 daily dose level. Less
prominent reactions included nausea and headache. No major antitumor
effects were observed. Pharmacokinetic studies in 15 patients at five
dose levels showed that the peak plasma concentration
( C max ) and areas under the plasma
concentration-time curve on day 1 were dose-proportional and were
similar to values obtained on days 15, 29, and 84. Unlike other
retinoids, LGD1550 did not induce its own metabolism, and there was
little evidence of drug accumulation. The
t 1/2 was approximately 5 h after both
the initial and repeated doses. We conclude that once-daily doses of
LGD1550 of up to 300 μg/m 2 are relatively well tolerated.
Additional clinical explorations are warranted, especially in patients
with cancers of the prostate, thyroid, head and neck, and cervix. |
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ISSN: | 1078-0432 1557-3265 |