Publications

Adult T-cell leukemia is a progressive disease produced by infection of mature T-cells with the human T-lymphotropic virus-I (HTLV-I). These retrovirus infected T-cells express large numbers of receptors for interleukin 2 (or T-cell growth factor). Due to the presence of these receptors, these leukemic T-cells can be selectively killed in vitro by monoclonal anti-interleukin 2 receptor antibody covalently linked to the A chain of the plant toxin, ricin (anti-TAC-A), suggesting that such immunotoxins may be useful in the therapy of this disease. In this report we demonstrate that the lysosomotropic agent ammonium chloride and the carboxylic ionophore monensin substantially potentiate the cytotoxicity of anti-TAC-A on HUT 102 cells, a long-term cultured HTLV-I infected T-cell line. Anti-TAC-A alone produces half-maximal inhibition of protein synthesis in HUT 102 cells at a concentration of 2.2 X 10(-10) M (the 50% inhibitor, concentration). Addition of ammonium chloride or monensin augments the potency of anti-TAC-A killing 100-fold (50% inhibitory concentration = 2.5 X 10(-12) M) and 400-fold (50% inhibitory concentration = 8 X 10(-13) M), respectively; furthermore, these agents accelerate rate of anti-TAC-A intoxication and increase the specific killing of interleukin 2 receptor-bearing leukemic cells. At concentrations which cause only minor harm to colony forming hematopoietic progenitor cells (granulocyte-erythroid, monocytic, megakaryocytic colony forming unit, granulocyte-macrophage colony forming unit, macrophage colony forming unit, and granulocyte colony forming unit), anti-TAC-A alone is able to eliminate greater than 99.99% of an HTLV-I infected T-cell population. In the presence of ammonium chloride or monensin, respectively, a 3.5- and 20-fold greater cytoreduction of HTLV-I infected T-cells is achieved. Combined treatment with anti-TAC-A and monensin may offer an efficient and highly selective means of purging bone marrow of patients with adult T-cell leukemia, which may then be used for autologous marrow transplantation.

Forty-three consecutive patients with acute inferior transmural myocardial infarction but no history or electrocardiographic evidence of prior myocardial infarction were evaluated prospectively to assess the clinical and prognostic importance of persistent precordial (V1-V4) ST segment depression. Patients were evaluated within 24 hr of admission by history, physical examination, cardiac enzyme levels, right heart catheterization, and radionuclide angiography; all were followed for 1 year. Ten of the 43 patients (group I) had persistent anterior precordial ST segment depression, defined as 1 mm or greater in one or more precordial leads (V1-V4) 24 hr after admission to the coronary care unit, and 33 patients (group II) did not. Clinical variables that differed between groups I and II, respectively, included mean age (67 +/- 9 [+/- 1 SD] vs 59 +/- 8 years; p less than .01), incidence of Killip class II to IV (100% vs 33%; p less than .001), and average peak creatine kinase concentration (2878 +/- 1139 vs 1511 +/- 1034 IU/liter; p less than .001). Hemodynamic differences between groups I and II included a higher pulmonary arterial wedge pressure (19 +/- 4 vs 11 +/- 5 mm Hg; p less than .001) and a lower cardiac index (2.0 +/- 0.5 vs 2.6 +/- 0.7 liters/min/m2; p less than .05). An evaluation of left ventricular ejection fraction and wall motion index by radionuclide angiography showed that group I had a lower ejection fraction (44 +/- 11% vs 53 +/- 10%; p less than .05) and higher wall motion index (1.7 +/- 0.4 vs 1.4 +/- 0.3; p less than .05) compared with group II.(ABSTRACT TRUNCATED AT 250 WORDS)