Factors associated with the therapeutic efficacy of retinoic acids on malignant lymphomas

We recently reported the successful use of retinoic acids in the treatment of refractory lymphoma. The biologic determinants predicting response of lymphomas to retinoic acid remain unknown. This study was conducted to explore this question using in vitro models. Sensitivity of representative lymphoma cells to 13-cis-retinoic acid was determined. Sensitive and resistant cell lines were then compared for their baseline and/or retinoic-acid-regulated expression of total cellular retinoic acid binding protein, retinoic acid receptor (RAR)-alpha, RAR-beta, RAR-gamma mRNA, retinoid X receptor (RXR)-alpha, RXR-beta, RXR-gamma mRNA, transforming growth factor (TGF)-beta 1 and TGF-beta 1 receptors, and Fas (Apo-I) mRNA. The results showed that four of five T, two of three Hodgkin's, and none of six B cell lymphoma cell lines were sensitive (IC30 < 1.5 mmol/L) to 13-cis-retinoic acid. Further analyses revealed several of the above-mentioned parameters may be relevant to retinoic acid sensitivity. Baseline expression of TGF-beta 1 receptors was present in all of the five sensitive cell lines examined, but in only one of the four resistant cell lines. The correlation of Fas expression and retinoic acid sensitivity was good for B cell lines, but not apparent for T cell or Hodgkin's cell lines. On exposure to retinoic acid, an immediate and prolonged upregulation of RAR-alpha mRNA expression, lasting for more than 12 hours, occurred in all sensitive cell lines, but only minimal or transient induction was seen in resistant cells. Together, these data suggested that; 1) retinoic acid has a preferential effect on T cell and Hodgkin's lymphoma cell lines; 2) autoregulation of RAR-alpha by retinoic acids, and the presence of TGF-beta 1 receptors may be relevant to the response of lymphomas to treatment with retinoic acids.