Kaposi sarcoma is a therapeutic target for vitamin D(3) receptor agonist.
Kaposi sarcoma (KS) is responsive to a number of different steroid hormones, such as glucocorticoids and retinoids. An active metabolite of vitamin D, 1alpha,25 dihydroxyvitamin D(3), was used to study the effect of this steroid hormone in KS. Steroid hormones exert their effect through their cognate nuclear receptors, which for vitamin D metabolites is the vitamin D receptor (VDR). It was first shown that KS cell lines and primary tumor tissue express high levels of VDR, whereas endothelial cells had minimal expression and fibroblasts had no expression. Second, KS cell growth was inhibited by VDR agonist 1alpha,25 dihydroxyvitamin D(3) with a 50% inhibitory concentration of 5 x 10 -8 mol/L, whereas endothelial cells and fibroblast cells showed no response. Studies on the mechanism of KS tumor growth inhibition by 1alpha,25 dihydroxyvitamin D(3) showed that production of autocrine growth factors interleukin (IL)-6 and IL-8 was reduced in a dose-dependent manner, whereas no effect was observed on vascular endothelial growth factor and basic fibroblast growth factor. Transcription initiated at the IL-6 promoter was repressed by VDR agonist. The DNA sequences required to mediate this repression were localized to nucleotides -225/-110 in the 5'-flanking region. The antitumor activity of VDR agonists was also confirmed in KS tumor xenograft and after topical application in patients with KS. 1alpha,25 Dihydroxyvitamin D(3) and its analogs may thus be candidates for clinical development in KS.
Masood
R
R
University of Southern California School of Medicine and Pathology, Norris Cancer Hospital and Research Institute, Los Angeles, CA, USA.
Nagpal
S
S
Zheng
T
T
Cai
J
J
Tulpule
A
A
Smith
D L
DL
Gill
P S
PS
D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D002117:Calcitriol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D015500:Chloramphenicol O-Acetyltransferase / Q000032:analysis / Q000235:genetics; D016228:Endothelial Growth Factors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics; D016209:Interleukin-8 / Q000235:genetics; D008222:Lymphokines / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009824:Ointments; D018167:Receptors, Calcitriol / Q000819:agonists* / Q000235:genetics; D012514:Sarcoma, Kaposi / Q000188:drug therapy / Q000473:pathology*; D012867:Skin / Q000473:pathology; D012878:Skin Neoplasms / Q000188:drug therapy / Q000473:pathology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000970:Antineoplastic Agents; D016228:Endothelial Growth Factors; D015850:Interleukin-6; D016209:Interleukin-8; D008222:Lymphokines; D009824:Ointments; D018167:Receptors, Calcitriol; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; C055085:calcipotriene; D015500:Chloramphenicol O-Acetyltransferase; D002117:Calcitriol