INFUSIONAL 8 CHLORO CYCLIC AMP IN TREATMENT OF MULTIPLE MYELOMA

输注 8 氯环安培治疗多发性骨髓瘤

• 批准号: 6263949
• 负责人: ANNE M TRAYNOR
• 金额: $ 2.05万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6263949
• 关键词: apoptosis; blood disorder chemotherapy; cardiac output; clinical research; cyclic AMP; drug resistance; glucocorticoids; heart rate; hormone regulation /control mechanism; human subject; human therapy evaluation; injection /infusion; interleukin 6; multiple myeloma; myocardium; neoplasm /cancer chemotherapy; neoplasm /cancer relapse /recurrence; nucleotide analog; tachycardia; vascular resistance; vascular smooth muscle

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.

该项目建立在越来越多的实验室证据的基础上，从而确定了淋巴样细胞系凋亡的诱导中不同但收敛的途径。 这些路径之一是由糖皮质激素受体结合引发的，并由环状AMP引发。 现在在我们的实验室观察到CAMP在诱导糖皮质激素敏感和糖皮质激素耐药性骨髓瘤细胞中诱导细胞死亡的一致性和明显的功效，我们提出了一项试验研究，以评估输液性二培养基cAMP作为复发和耐药性脊髓瘤作为单一药物。 我们的研究表明，与骨髓瘤细胞系中糖皮质激素诱导的细胞死亡方法不同，营地暴露诱导的细胞死亡不会因IL-6的外源性供应而抵抗或阻止。 以前在这里用于治疗充血性心力衰竭的剂量以前使用了Dibutyryl CAMP输注。 正如人们可以从已知的血管平滑肌和心肌活动范围内预测的那样，它与心率的增加，加里迪克输出量的增加以及全身性血管耐药性的降低有关。 在先前的药理学试验中，除了心动过速外，它与低血压或心律不齐有关。我们的计划是在复发或难治性的骨髓瘤第一线治疗的患者中使用这种疗法。 在这种情况下，最好的单个代理是地塞米松，它提供了30％的响应。 由于我们的实验室数据表明，仅在诱导骨髓瘤细胞系中诱导细胞死亡的地塞米松的优势中，我们希望仅对该药物的任何类似的效率率。