Combinational treatment with retinoic acid derivatives in non-small cell lung carcinoma in vitro.
The growth inhibitory effects of four retinoic acid (RA) derivatives, 9-cis RA, 13-cis RA, N-(4-hydroxyphenyl) retinamide (4-HPR), and all-trans retinoic acid (ATRA) were compared. In addition, the effects of various combinations of these four agents were examined on non-small cell lung carcinoma (NSCLC) cell-lines, and on the expressions of retinoic acid receptors (RARs) and retinoid X receptors (RXRs) on these cells. At the clinically achievable concentration of 1 microM, only 4-HPR inhibited the growths of H1299 and H460 cells-lines. However, retinoic acid receptor beta(RAR beta) expression was up-regulated on H460 and H1299 cells treated with 1 microM of ATRA, 13-cis RA, or 9-cis RA. All NSCLC cell lines showed growth inhibition when exposed sequentially to 1 microM ATRA and 0.1 microM 4-HPR. In particular, sequential treatment with 1 microM ATRA or 13-cis RA and 4-HPR markedly inhibited H1703 cell growth; these cells exhibited no basal RAR beta expression and were refractory to 4-HPR. However, in NSCLC cell lines that expressed RAR beta, the expressional levels of RAR beta were up-regulated by ATRA alone and by sequential treatment with ATRA and 4-HPR. 4-HPR was found to be the most active of the four agents in terms of NSCLC growth-inhibition. Moreover, sequential treatments with ATRA or 13-cis RA followed by 4-HPR were found to have synergistic growth-inhibitory effects and to regulate RAR expression.
Choi
Eun Jung
EJ
Department of Internal Medicine and Brain Korea 21 Program for Biomedical Sciences, Korea University College of Medicine, Seoul, Korea.
Whang
Young Mi
YM
Kim
Seok Jin
SJ
Kim
Hyun Jin
HJ
Kim
Yeul Hong
YH
D000077556:Alitretinoin; D001483:Base Sequence; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D017931:DNA Primers / Q000235:genetics; D004359:Drug Therapy, Combination; D017313:Fenretinide / Q000008:administration & dosage; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015474:Isotretinoin / Q000008:administration & dosage; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics; D047488:Retinoid X Receptors / Q000235:genetics; D014212:Tretinoin / Q000008:administration & dosage / Q000031:analogs & derivatives*
D017931:DNA Primers; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; C082925:retinoic acid receptor beta; D017313:Fenretinide; D000077556:Alitretinoin; D014212:Tretinoin; D015474:Isotretinoin