INVIVO SENSITIVITY AND RESISTANCE OF CHRONIC MYELOGENOUS LEUKEMIA-CELLS TO ALPHA-INTERFERON - CORRELATION WITH RECEPTOR-BINDING AND INDUCTION OF 2',5'-OLIGOADENYLATE SYNTHETASE

  • 1 September 1986
    • journal article
    • research article
    • Vol. 46  (9) , 4848-4852
Abstract
Fourteen patients with chronic myelogenous leukemia were treated with partially pure leukocyte interferon (HuIFN.alpha.). The binding of recombinant leukocytes clone A IFN and the induction of 2'',5''-oligoadenylate synthetase (2,5A) in peripheral blood cells were studied to determine whether they correlate with clinical response to IFN therapy. The mean pretherapy binding of radiolabeled recombinant leukocyte clone A IFN to peripheral blood cells was 0.053 .+-. 0.02 (SE) fmol (53 .+-. 20 amol)/106 cell and 0.049 .+-. 0.015 fmol/106 cells insensitive and resistant patients, respectively. Twenty-four h after the first HuIFN.alpha. clone, the binding of recombinant leukocyte clone A IFN decreased 3- to 8-fold in both sensitive and resistant patients. The activity to 2,5A synthetase was induced approximately 100-fold in sensitive patients from a pretherapy mean of 3 .+-. 2 nmol/mg to a maximum of 317 .+-. 184 nmol/mg during therapy. In contrast, 2,5A synthetase was induced from a pretherapy mean 0.9 .+-. 0.9 nmol/mg to only 6.7 .+-. 4.9 nmol/mg in resistant patients. In two patients originally sensitive to HuIFN.alpha. who developed resistance to therapy, receptors were present in both sensitive and resistant disease stages and appeared to down regulate with therapy regardless of response. In these two patients, 2,5A synthetase was significantly induced with therapy in the sensitive stage but not in the resistant stage. This study shows that lack of clinical response to interferon therapy may coincide with failure to induce 2,5A synthetase activity. This suggest that resistance to .alpha.-interferon therapy may be mediated by events beyond receptor binding resulting in a failure to induce enzymes reasonable for mediation of interferon antiproliferative effects.