Hait W N, Byrne T N, Piepmeier J, Durivage H J, Choudhury S, Davis C A, Gates J A
Yale University School of Medicine, Department of Medicine, New Haven, Connecticut.
Cancer Res. 1990 Oct 15;50(20):6636-40.
Glioblastoma multiforme is a fatal malignancy of the central nervous system, demanding new methods of treatment. The combination of a calmodulin antagonist with bleomycin has shown synergistic activity in several preclinical models and has been evaluated in a Phase I clinical trial. Since phenothiazines reach high concentrations in the central nervous system, and bleomycin has been reported to have antitumoral activity as well, we studied this combination in a Phase II clinical trial. In addition, we purified calmodulin from normal brain and malignant gliomas to determine its biochemical and pharmacological characteristics. Seventeen patients were entered onto this study and all were evaluable. There were no partial or complete responses. There was one case of fatal pulmonary toxicity in a patient showing an objective tumor response. Otherwise, the treatment was well tolerated. Calmodulin purified from the normal brain and gliomas of patients undergoing resection was identical to each other and to calmodulin prepared from rat cerebrum and glioma. These characteristics included elution from a TSK phenyl high pressure liquid chromatography column, migration on 16% sodium dodecyl sulfate gels, amino acid composition, and inhibition by drugs. Therefore, the failure of this combination therapy was not due to a difference in human glioma calmodulin as compared to previously reported studies with calmodulin from murine sources.
多形性胶质母细胞瘤是中枢神经系统的一种致命恶性肿瘤，需要新的治疗方法。钙调蛋白拮抗剂与博来霉素的联合在几种临床前模型中已显示出协同活性，并已在一项I期临床试验中进行了评估。由于吩噻嗪类药物在中枢神经系统中能达到高浓度，且据报道博来霉素也具有抗肿瘤活性，我们在一项II期临床试验中研究了这种联合用药。此外，我们从正常脑和恶性胶质瘤中纯化了钙调蛋白，以确定其生化和药理学特性。17名患者进入了这项研究，且所有患者均可评估。没有部分或完全缓解的情况。有1例出现客观肿瘤反应的患者发生了致命的肺部毒性。否则，该治疗耐受性良好。从接受切除术患者的正常脑和胶质瘤中纯化的钙调蛋白彼此相同，且与从大鼠大脑和胶质瘤中制备的钙调蛋白相同。这些特性包括从TSK苯基高压液相色谱柱上洗脱、在16%十二烷基硫酸钠凝胶上的迁移、氨基酸组成以及药物抑制作用。因此，与先前报道的使用来自鼠源钙调蛋白的研究相比，这种联合治疗的失败并非由于人胶质瘤钙调蛋白存在差异。
