According to an in vitro study, treating leukemic B- and T-cells with Ligand's bexarotene (Targretin) made the cancerous cells more susceptible to killing by denileukin diftitox (ONTAK).

"This study demonstrates that bexarotene and other RXR modulators 'upregulate,' or make more plentiful, high-affinity interleukin-2 (IL-2) receptor expression on leukemic B- and T-cells, thus making them more susceptible to killing by denileukin diftitox," said co-author Francine Foss, associate professor of medicine and director of the lymphoma program at the Tufts New England Medical Center in Boston. "These results suggest that the clinical efficacy of ONTAK may be enhanced by adding Targretin to therapy, and Phase I/II trials to further elucidate this concept are underway."

IL-2 receptors are commonly expressed on the surface of cancerous cells. The receptor consists of three sub-units: p55 (also called IL-2R alpha or CD25), p75 (IL-2R beta/CD122) and p64 (IL-2R gamma/CD132). "High affinity" receptors are composed of all three sub-units. Previous in vitro studies have demonstrated that treatment with ONTAK, a genetically engineered fusion protein, is most efficient in leukemia and lymphoma cells expressing the high-affinity IL-2 receptor.

Targretin and other RXR modulators modulate immune response by binding to retinoid receptors within cells that play a role in regulating cell differentiation, growth and apoptosis. Targretin binds selectively to retinoid X receptors.

In the study, the researchers exposed B- and T-leukemia cell lines and fresh leukemia cells to two low concentrations of bexarotene and alitretinoin (Panretin) for 48 hours. Both bexarotene and alitretinoin up-regulated expression of p55 and p75 at least four-fold in T-cells and fresh leukemia cells. In B cells, bexarotene and alitretinoin increased expression of p75 but not p55.

The researchers then exposed the cells to denileukin diftitox, measuring protein synthesis inhibition and cell growth. Protein synthesis inhibition reflects the efficiency with which the diphtheria toxin portion of denileukin diftitox is internalized in cancerous cells. In T cells, protein synthesis was inhibited by 50-70% after exposure to bexarotene or alitretinoin. In B-cells, alitretinoin inhibited protein synthesis by 35%, compared to more than 50% with bexarotene. The researchers also measured cytotoxicity directly, and concluded that bexarotene enhanced the cytotoxicity of ONTAK more than alitretinoin did. Specifically, bexarotene increased the number of cells killed by ONTAK by between 23% and 48%.