New Retinoid Shows Promise as a Nontoxic Chemopreventive Agent

May 1, 1997
Oncology NEWS International, Oncology NEWS International Vol 6 No 5, Volume 6, Issue 5

SAN DIEGO--A retinoid with specificity for the RXR receptor has shown potential as a virtually nontoxic chemo-preventive agent for breast cancer.

SAN DIEGO--A retinoid with specificity for the RXR receptor has shownpotential as a virtually nontoxic chemo-preventive agent for breast cancer.

The RXR ligand LGD1069 inhibited tumor formation in laboratory animalsto the same degree as did tamoxifen (Nolvadex). The tumor inhibition occurredwith no apparent signs of toxicity. These initial results have providedthe basis for ongoing phase II/III trials of the synthetic retinoid, Dr.Marco M. Gottardis said at a general session of the San Antonio BreastCancer Symposium.

The findings come from evaluations of animals that underwent NMU tumorinduction, a model for hormone-dependent breast cancer. A week after exposureto NMU, the animals were given either LGD1069 (Targretin), at a dose of30 or 100 mg/kg/day, or tamoxifen at a dose of 50 or 150 mg/kg/day. Controlanimals received no chemoprevention.

After 12 weeks, the control animals had a 100% incidence of mammarycarcinoma, averaging three tumors per animal. The lower dose of tamoxifenresulted 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 effectsof high-dose tamoxifen. Animals treated with high-dose tamoxifen or LGD1069averaged fewer than 0.5 tumors, said Dr. Gottardis, a senior research scientistat 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 otherretinoids. The animals also did not have weight loss, whereas tamoxifen-treatedanimals had significant weight loss.

No Effect on Hormonal Milieu

LGD1069 had no effect on the animals' hormonal milieu. Compared withcontrols, animals treated with the retinoid had no changes in levels ofestradiol, progesterone, or prolactin.

Interestingly, Dr. Gottardis said, LGD1069 appeared to have reduceduterine proliferation (wet weight), compared with control animals. Agentsthat have antiestrogenic effects, such as tamoxifen, have been shown toincrease uterine wet weight. "This difference is an interesting findingand might point to some mechanisms about how inhibition of tumor growthoccurs with LGD1069," he said.