Lani
03-13-2007, 10:44 AM
...talking about Targetin(already FDA approved for Tcell cutaneous lymphoma)
Previous work in our laboratory showed that the naturally
occurring retinoid 9-cis RA is a promising agent for treatment
and prevention of breast cancer (17). However, in human clinical
trials, 9-cis RA has been found to have significant toxicity (34).
Therefore, receptor-selective retinoids that have reduced toxicity
are now being developed as potential chemopreventive agents.
We have previously shown that RXR-selective retinoids suppress
tumorigenesis with minimal toxicity compared with RAR-
selective retinoids (18). In addition, rexinoids can significantly
prevent estrogen receptor–negative mammary tumor develop-
ment with minimal toxicity in MMTV-erbB2 transgenic mice (16).
Suh et al. (35) and Rendi et al. (36) previously reported that
another rexinoid, LG100268, was active for prevention and
treatment of chemically induced estrogen receptor–positive
breast carcinomas in rats by promoting apoptosis. Furthermore,
the ability of this rexinoid to promote apoptosis was increased
by combining it with the selective estrogen receptor modulator
arzoxifene (36). This report suggested that LG100268, in
combination with arzoxifene, induced transforming growth factor
h, inhibited nuclear factor nB signaling, and induced phospha-
tase and tensin homologue (PTEN) expression. All of these
changes would contribute to the cancer-preventive activity of this
combination....
suggest that the combination of LGD1069 plus COX-2 inhibitors
may be particularly effective for prevention of human breast
cancer.
This study has identified rexinoid-modulated genes in HMECs
using oligonucleotide microarrays. It is possible that additional
genes are modul ated by rexinoi ds in vivo because gene
expression changes induced by rexinoid treatment of breast
cells in culture may not completely reflect those modulated
in vivo . For example, some genes may be modulated through
epithelial-stromal cell interaction. Such rexinoid-regulated genes
would not have been identified in our in vitro screen. However,
the candidate biomarkers (SCD-1, ODC1, COX-2, and cyclin D1)
identified from our in vitro studies were also modulated in vivo
in the MMTV-erbB2 mice. Thus, the rexinoid-regulated bio-
markers identified in these studies represent potentially useful
biomarkers for testing rexinoids in future clinical studies.
The protein products of these genes could be (a ) biomarkers
of exposure to rexinoids (keratins, DEPP, and SCD-1), ( b )
biomarkers involved in suppressing breast cell proliferation
(RARh, IGFBP-6, p27, and PTEN), or (c ) important growth
regulator y molecules that could ser ve as targets of future
therapy (COX-2, collagenase).
Previous work in our laboratory showed that the naturally
occurring retinoid 9-cis RA is a promising agent for treatment
and prevention of breast cancer (17). However, in human clinical
trials, 9-cis RA has been found to have significant toxicity (34).
Therefore, receptor-selective retinoids that have reduced toxicity
are now being developed as potential chemopreventive agents.
We have previously shown that RXR-selective retinoids suppress
tumorigenesis with minimal toxicity compared with RAR-
selective retinoids (18). In addition, rexinoids can significantly
prevent estrogen receptor–negative mammary tumor develop-
ment with minimal toxicity in MMTV-erbB2 transgenic mice (16).
Suh et al. (35) and Rendi et al. (36) previously reported that
another rexinoid, LG100268, was active for prevention and
treatment of chemically induced estrogen receptor–positive
breast carcinomas in rats by promoting apoptosis. Furthermore,
the ability of this rexinoid to promote apoptosis was increased
by combining it with the selective estrogen receptor modulator
arzoxifene (36). This report suggested that LG100268, in
combination with arzoxifene, induced transforming growth factor
h, inhibited nuclear factor nB signaling, and induced phospha-
tase and tensin homologue (PTEN) expression. All of these
changes would contribute to the cancer-preventive activity of this
combination....
suggest that the combination of LGD1069 plus COX-2 inhibitors
may be particularly effective for prevention of human breast
cancer.
This study has identified rexinoid-modulated genes in HMECs
using oligonucleotide microarrays. It is possible that additional
genes are modul ated by rexinoi ds in vivo because gene
expression changes induced by rexinoid treatment of breast
cells in culture may not completely reflect those modulated
in vivo . For example, some genes may be modulated through
epithelial-stromal cell interaction. Such rexinoid-regulated genes
would not have been identified in our in vitro screen. However,
the candidate biomarkers (SCD-1, ODC1, COX-2, and cyclin D1)
identified from our in vitro studies were also modulated in vivo
in the MMTV-erbB2 mice. Thus, the rexinoid-regulated bio-
markers identified in these studies represent potentially useful
biomarkers for testing rexinoids in future clinical studies.
The protein products of these genes could be (a ) biomarkers
of exposure to rexinoids (keratins, DEPP, and SCD-1), ( b )
biomarkers involved in suppressing breast cell proliferation
(RARh, IGFBP-6, p27, and PTEN), or (c ) important growth
regulator y molecules that could ser ve as targets of future
therapy (COX-2, collagenase).