INFUSIONAL 8 CHLORO CYCLIC AMP IN TREATMENT OF MULTIPLE MYELOMA

这个项目建立在越来越多的实验室证据，确定不同的，但收敛的途径诱导淋巴细胞系的凋亡。 这些途径之一是由糖皮质激素受体结合和环AMP启动。 现在在我们的实验室中观察到cAMP在糖皮质激素敏感和糖皮质激素耐药骨髓瘤细胞中诱导细胞死亡的一致和显著的功效，我们提出了一项初步研究，评估输注双丁酰cAMP作为复发和耐药骨髓瘤的单一药物。 我们的研究表明，与骨髓瘤细胞系中糖皮质激素诱导细胞死亡的方法不同，cAMP暴露诱导的细胞死亡不受外源性IL-6供应的抵抗或阻止。 双丁酰cAMP输注先前已在治疗充血性心力衰竭中以本文所用的剂量使用。 正如人们从其对血管平滑肌和心肌的已知活性范围所预测的那样，它与心率增加、心输出量增加和全身血管阻力降低有关。 在先前的药理学试验中，除窦性心动过速外，它与低血压或心律失常无关。我们的计划是在骨髓瘤一线治疗复发或难治的患者中使用这种疗法。 在这种情况下，最好的单一药物是地塞米松，它提供了30%的反应。 由于我们的实验室数据表明，在诱导骨髓瘤细胞系细胞死亡方面优于单独使用地塞米松，我们希望了解单独使用该药物的任何类似效率。

This project builds upon growing laboratory evidence identifying distinct, but convergent pathways in the induction of apoptosis in lymphoid cell lines. One of these paths is initiated by glucocorticoid receptor binding and one initiated by cyclic AMP. Having now observed in our laboratory a consistent and marked efficacy of cAMP in inducing cell death in glucocorticoid-sensitive and glucocorticoid-resistant myeloma cells, we propose a pilot study evaluating infusional dibutyryl cAMP as a single agent in relapsed and resistant myeloma. Our studies have shown that, unlike the method of cell death induced by glucocorticoids in myeloma cell lines, the cell death induced by cAMP exposure is not resisted or deterred by exogenous supply of IL-6. Dibutyryl cAMP infusion has been previously employed at the doses utilized here in the treatment of congestive heart failure. As one would predict from its known range of activities on vascular smooth muscle and myocardium, it is associated with an increase in heart rate, an increase in caridac output, and a decrease in systemic vascular resistance. In prior pharmacologic trials it has not been associated with hypotension or arrhythmia other than sinus tachycardia. Our plan is to utilize this therapy in patients who have relapsed or been refractory to first line therapy for myeloma. The best single agent in this setting is dexamethasone, which offers a 30% response. Since our laboratory data suggest superiority to dexamethasone alone in inducing cell death in myeloma cell lines, we hope to appreciate any similar rate of efficiency for this agent alone.