FACTORS ASSOCIATED WITH THE THERAPEUTIC EFFICACY OF RETINOIC ACIDS ONMALIGNANT-LYMPHOMAS

We recently reported the successful use of retinoic acids in the treat ment of refractory lymphoma. The biologic determinants predicting resp onse of lymphomas to retinoic acid remain unknown. This study was cond ucted to explore this question using in vitro models. Sensitivity of r epresentative lymphoma cells to 13-cis-retinoic acid was determined. S ensitive and resistant cell lines were then compared for their baselin e and/or retinoic acid-regulated expression of total cellular retinoic acid binding protein, retinoic acid receptor (RAR)-alpha, RAR-beta, R AR-gamma mRNA, retinoid X receptor (RXR)-alpha, RXR-beta, RXR-gamma mR NA, 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 t hree Hodgkin's, and none of six B cell lymphoma cell lines were sensit ive (IC50 < 1.5 mmol/L) to 13-cis-retinoic acid. Further analyses reve aled several of the above-mentioned parameters may be relevant to reti noic 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 expressi on and retinoic acid sensitivity was good for B cell lines, but not ap parent for T cell or Hodgkin's cell lines. On exposure to retinoic aci d, an immediate and prolonged upregulation of RAR-alpha mRNA expressio n, lasting for more than 12 hours, occurred in all sensitive cell line s, but only minimal or transient induction was seen in resistant cells . Together, these data suggested that: 1) retinoic acid has a preferen tial effect on T cell and Hodgkin's lymphoma cell lines: 2) autoregula tion of RAR-alpha by retinoic acids, and the presence of TGF-beta 1 re ceptors may be relevant to the response of lymphomas to treatment with retinoic acids.