Nonclassical retinoids and lung carcinogenesis.
The retinoids are natural and synthetic derivatives of vitamin A. These cancer therapeutic and chemopreventive agents exert antiproliferative, differentiation-inducing, proapoptotic, and other biologic effects. The retinoids act through nuclear retinoid receptors to activate target genes that signal biologic effects. Agents that specifically activate the nuclear retinoid X receptors (RXRs) are known as rexinoids. Rexinoid growth suppression of human bronchial epithelial cells was linked to triggering of G1 cell cycle arrest, concomitant growth suppression, and a decrease in expression of G1 cyclins through activation of a proteasome-dependent degradation pathway. Clinical studies have demonstrated prolonged survival of subsets of patients with non-small-cell lung cancer (NSCLC) treated with rexinoids as single agents or as part of combination regimens. The critical role of RXR in downstream signaling makes rexinoids especially attractive agents to consider in combination therapy. There is encouraging evidence for therapeutic benefit of combination regimens of rexinoids with other targeted agents, such as epidermal growth factor receptor inhibitors, and with chemotherapy. Results from randomized phase III clinical trials in NSCLC will ultimately determine the impact for rexinoid-based therapy or chemoprevention for lung cancer.
Dragnev
Konstantin H
KH
Hematology/Oncology Section, Department of Medicine, Dartmouth-Hitchcock Medical Center, Hanover, NH 03756, USA. dragnev@dartmouth.edu
Petty
W Jeffrey
WJ
Ma
Yan
Y
Rigas
James R
JR
Dmitrovsky
Ethan
E
D016588:Anticarcinogenic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000077610:Bexarotene; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D018168:Receptors, Retinoic Acid / Q000819:agonists; D012176:Retinoids / Q000378:metabolism / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology / Q000627:therapeutic use*; D025801:Ubiquitin / Q000378:metabolism
D016588:Anticarcinogenic Agents; D016213:Cyclins; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D013764:Tetrahydronaphthalenes; D025801:Ubiquitin; D000077610:Bexarotene; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases