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Blood, 1 November 2000, Vol. 96, No. 9, pp. 3188-3194
NEOPLASIA
Kaposi sarcoma is a therapeutic target for vitamin D3
receptor agonist
Rizwan Masood,
Sunil Nagpal,
Tong Zheng,
Jie Cai,
Anil Tulpule,
D. Lynne Smith, and
Parkash S. Gill
From the University of Southern California School of
Medicine and Pathology, Norris Cancer Hospital and Research Institute,
Los Angeles, CA, and from Allergan Pharmaceuticals, Irvine, CA.
Kaposi sarcoma (KS) is responsive to a number of different steroid
hormones, such as glucocorticoids and retinoids. An active metabolite
of vitamin D, 1 ,25 dihydroxyvitamin D3, 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 1,25
dihydroxyvitamin D3 with a 50% inhibitory concentration of
5 × 10  8 mol/L, whereas endothelial cells and fibroblast
cells showed no response. Studies on the mechanism of KS tumor growth
inhibition by 1,25 dihydroxyvitamin D3 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. 1,25
Dihydroxyvitamin D3 and its analogs may thus be candidates
for clinical development in KS.
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