SAN DIEGO--A retinoid with specificity for the RXR receptor has shown
potential as a virtually nontoxic chemo-preventive agent for breast cancer.
The RXR ligand LGD1069 inhibited tumor formation in laboratory animals
to the same degree as did tamoxifen (Nolvadex). The tumor inhibition occurred
with no apparent signs of toxicity. These initial results have provided
the basis for ongoing phase II/III trials of the synthetic retinoid, Dr.
Marco M. Gottardis said at a general session of the San Antonio Breast
The findings come from evaluations of animals that underwent NMU tumor
induction, a model for hormone-dependent breast cancer. A week after exposure
to NMU, the animals were given either LGD1069 (Targretin), at a dose of
30 or 100 mg/kg/day, or tamoxifen at a dose of 50 or 150 mg/kg/day. Control
animals received no chemoprevention.
After 12 weeks, the control animals had a 100% incidence of mammary
carcinoma, averaging three tumors per animal. The lower dose of tamoxifen
resulted in a small reduction in tumor incidence, compared with controls,
while the higher dose was associated with a 20% tumor incidence.
Both doses of LGD1069 matched or exceeded the chemopreventive effects
of high-dose tamoxifen. Animals treated with high-dose tamoxifen or LGD1069
averaged fewer than 0.5 tumors, said Dr. Gottardis, a senior research scientist
at Ligand Pharmaceuticals in San Diego.
Of note, the animals treated with LGD1069 had no mucocutaneous, skeletal,
or dermatologic toxicity, which has often proved dose limiting with other
retinoids. The animals also did not have weight loss, whereas tamoxifen-treated
animals had significant weight loss.
No Effect on Hormonal Milieu
LGD1069 had no effect on the animals' hormonal milieu. Compared with
controls, animals treated with the retinoid had no changes in levels of
estradiol, progesterone, or prolactin.
Interestingly, Dr. Gottardis said, LGD1069 appeared to have reduced
uterine proliferation (wet weight), compared with control animals. Agents
that have antiestrogenic effects, such as tamoxifen, have been shown to
increase uterine wet weight. "This difference is an interesting finding
and might point to some mechanisms about how inhibition of tumor growth
occurs with LGD1069," he said.