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的基础上，确定了诱导淋巴细胞系凋亡的不同但趋同的途径。其中一条途径是由糖皮质激素受体结合启动的，另一条是由环磷酸腺苷启动的。在我们实验室观察到cAMP在诱导糖皮质激素敏感和耐药骨髓瘤细胞死亡方面有一致和显著的疗效后，我们建议进行一项初步研究，评估静脉注射二丁酰cAMP作为复发和耐药骨髓瘤的单一药物。我们的研究表明，与糖皮质激素诱导骨髓瘤细胞系细胞死亡的方法不同，cAMP暴露诱导的细胞死亡不被外源IL-6的供应所抵抗或阻止。二丁酰环磷腺苷输注以前曾用于治疗充血性心力衰竭。根据已知的血管平滑肌和心肌活动范围，人们可以预测，它与心率增加、心脏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复发或对一线治疗无效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，地塞米松优于单独使用，因此我们希望评价单独使用地塞米松的类似效率。

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.