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，这些证据确定了诱导淋巴样细胞系凋亡的不同但趋同的途径。 其中一种途径是由糖皮质激素受体结合启动的，另一种是由环 AMP 启动的。 现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死亡方面具有一致且显着的功效，因此我们提出了一项初步研究，评估输注二丁酰 cAMP 作为复发性和耐药性骨髓瘤的单药。 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会被外源供应的IL-6抵抗或阻止。 二丁酰 cAMP 输注先前已按此处使用的剂量用于治疗充血性心力衰竭。 正如人们从其对血管平滑肌和心肌的已知活动范围所预测的那样，它与心率增加、心输出量增加和全身血管阻力降低有关。 在之前的药理学试验中，除窦性心动过速外，它与低血压或心律失常无关。我们的计划是将这种疗法用于骨髓瘤一线治疗复发或难治的患者。 在这种情况下，最好的单一药物是地塞米松，其反应率为 30%。 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，因此我们希望了解单独使用该药物的类似效率。