Publications

Transferrin receptor expression is essential for the proliferation of both normal and malignant T cells. While transferrin receptor expression in normal T cells is tightly coupled to interleukin-2 receptor expression, transferrin receptor expression in malignant cells is usually constitutive and is released from this constraint. Temporally, the appearance of these membrane receptors is preceded by changes in the expression of the proto-oncogenes c-myc and c-myb. In addition, although an increase in the level of intracellular free calcium occurs early in the sequence of T-cell activation, the activation events dependent on this calcium flux have not been resolved. In the present study we report that diltiazem, an ion channel-blocking agent that inhibits calcium influx, arrested the growth in vitro of both normal and malignant human T cells in the G1 phase of the cell cycle. However, diltiazem did not inhibit the expression of c-myc or interleukin-2 receptor mRNA and protein in normal mitogen-activated T cells or the constitutive expression of c-myc and c-myb mRNA in malignant T cells (T acute lymphoblastic leukemia cells). In contrast, diltiazem prevented the induction of transferrin receptor (mRNA and protein) in normal T cells and caused a progressive loss of transferrin receptor (mRNA and protein) in malignant T cells. These data demonstrate that diltiazem can dissociate several growth-related processes normally occurring in G1 and thereby disrupt the biochemical cascade leading to cell proliferation.

Exposure of guinea pigs to toluene diisocyanate (TDI) causes an increase in airway responsiveness to inhaled acetylcholine. This increased airway responsiveness is temporally associated with an increase in polymorphonuclear leukocytes (PMN) in the tracheal wall. To determine whether PMN play a mechanistic role in this increase in acetylcholine responsiveness, we studied the effects of PMN depletion on this response with 2 different cytotoxic drugs, hydroxyurea and cyclophosphamide. Airway responsiveness was measured in untreated, hydroxyurea-treated, or cyclophosphamide-treated animals while they breathed spontaneously or during mechanical ventilation through a tracheostomy. In untreated animals, exposure to TDI caused a significant increase in airway responsiveness to acetylcholine for both spontaneously breathing and anesthetized and ventilated animals. This TDI-induced increase in airway responsiveness was associated with a significant influx of PMN into both the extravascular and intravascular trachea. Treatment with hydroxyurea, to reduce PMN counts in the bloodstream to less than 200/mm3, inhibited both the TDI-induced increase in airway responsiveness and the TDI-induced influx of PMN into the trachea of both spontaneously breathing and mechanically ventilated animals. In mechanically ventilated animals, treatment with cyclophosphamide, until PMN counts in the bloodstream were less than 200/mm3, also inhibited the influx of PMN into the trachea but did not inhibit the TDI-induced increase in airway responsiveness. These results suggest that PMN are not necessary for the TDI-induced increase in airway responsiveness and that hydroxyurea inhibits this effect by a mechanism other than PMN depletion.