Bernie, the abstract for the NCI article that Henry posted yesterday describing the use of panretin and raloxifene is not available for viewing but one employing another antiestrogen compound one is. Combined use of panretin and tamoxifen proved highly effective in preventing induced breast tumors in rats. This is the synergism to which Henry refers.
Cancer Res 1994 Sep 1;54(17):4614-4617
Prevention of breast cancer in the rat with 9-cis-retinoic acid as a single
agent and in combination with tamoxifen.
Anzano MA, Byers SW, Smith JM, Peer CW, Mullen LT, Brown CC, Roberts AB, Sporn MB
Laboratory of Chemoprevention, National Cancer Institute, Bethesda, Maryland 20892.
We show that 9-cis-retinoic acid (9cRA) is a potent inhibitor of mammary carcinogenesis induced by N-nitroso-N-methylurea
in Sprague-Dawley rats. Rats were first treated with a single dose of N-nitroso-N-methylurea (50 mg/kg body weight) and
then fed non-toxic levels of 9cRA (120 or 60 mg/kg of diet). 9cRA was highly effective in reducing tumor incidence, average
number of tumors per rat, and average tumor burden, as well as extending tumor latency. The combination of 9cRA with low
levels of tamoxifen (TAM; fed at either 1.0 or 0.5 mg/kg of diet) was particularly effective; addition of 9cRA to a TAM
regimen doubled the number of animals that were tumor-free at autopsy and significantly diminished tumor number and tumor
burden. For suppression of carcinogenesis in vivo, 9cRA was much more potent than all-trans-retinoic acid, both as a single
agent or in combination with TAM, although both retinoids had equivalent inhibitory effects on DNA synthesis in cultured
human breast cancer cell lines. Both 9cRA and all-trans-retinoic acid induce the expression of the adhesion molecule,
E-cadherin, in the SK-BR-3 cell line. We suggest that clinical evaluation of the combination of 9cRA and TAM, either for
chemoprevention or for adjuvant therapy, should be considered.
PMID: 8062253, UI: 94340584
ncbi.nlm.nih.gov
The last few sentences in the following abstract again suggest the synergistic possibilities in treating treating breast cancer , ER+ as well as ER-s that express RAR alpha, with RAR and RXR ligands and antiestrogens. Panretin was also used in this study.
Cancer Res 1997 Jul 1;57(13):2642-2650
Retinoic acid receptor alpha expression correlates with retinoid-induced
growth inhibition of human breast cancer cells regardless of estrogen
receptor status.
Fitzgerald P, Teng M, Chandraratna RA, Heyman RA, Allegretto EA
Department of Retinoid Research, Ligand Pharmaceuticals, Inc., San Diego, California 92121, USA.
Retinoic acid receptor (RAR) alpha has been shown to play a role in retinoid-induced growth inhibition of human breast cancer
cell lines that express the estrogen receptor (ER). The dogma in the field has been that ER-positive breast cancer cell lines
respond to retinoid treatment because they express RAR alpha, whereas ER-negative breast cancer cell lines are refractory to
retinoid treatment and have been thought to express little or no RAR alpha. We set out to test several ER-negative breast
cancer cell lines for expression of RAR alpha protein and responsiveness to retinoids in growth inhibition assays. Of six
ER-negative breast cancer cell lines that were tested, one (SK-BR-3) had high levels of RAR alpha protein as measured by
ligand-binding immunoprecipitation (approximately 55 fmol/mg protein) and also displayed sensitivity to growth inhibition by
retinoids (9-cis-retinoic acid; EC50, approximately 3 nM). These cells were more sensitive than an ER-positive cell line,
T-47D, which expressed approximately 35 fmol RAR alpha/mg total protein (9-cis retinoic acid; EC50, approximately
50-100 nM). Another ER-negative cell line, Hs578T, also expressed RAR alpha (approximately 23 fmol/mg) and was
sensitive to retinoid-induced growth inhibition, albeit to a lesser extent than SK-BR-3 or T-47D cells. In contrast, the other
ER-negative cell lines tested expressed low (<10 fmol/mg) or no detectable levels of RAR alpha protein and also did not
respond to retinoids in growth inhibition assays. A RAR alpha agonist displayed 100 times greater potency than a RARgamma
agonist in growth inhibition of both T-47D and SK-BR-3 cells, suggesting RAR alpha involvement in the process.
Furthermore, a RAR alpha antagonist completely abolished the growth inhibition induced by RAR agonists, implying that the
activity of the agonists is exerted solely through RAR alpha, not RARgamma, which is also expressed in both cell lines.
Additionally, although retinoid X receptor (RXR) compounds are weakly active in growth inhibition of the RAR alpha-positive
cell lines, they markedly increased the growth-inhibitory activity of RAR ligands. RXR compounds also potentiated the action
of the antiestrogen 4-hydroxytamoxifen to inhibit the growth of T-47D cells. These findings have clinical ramifications in that
patients with ER-negative tumors that are RAR alpha positive may be candidates for retinoid therapy. Additionally,
combinations of RXR ligands with RAR ligands (especially RAR alpha agonists) and/or antiestrogens may have utility in the
treatment of breast cancer.
PMID: 9205071, UI: 97349067
ncbi.nlm.nih.gov |
