BACKGROUND & AIMS:
:A number of factors have been proposed as potential mediators of the syndrome of humoral hypercalcemia of malignancy (HHM), but to date no firm cause-and-effect relationship has been established. We attempted to establish such a relationship by determining whether the presence or absence of adenylate cyclase-stimulating activity (ACSA) in the media of cultured tumor cells predicted the occurrence of the syndrome of HHM when these cell lines were grown in nude mice in vivo. Conditioned media from 35 human renal carcinoma cell lines were surveyed for ACSA in the PTH-sensitive rat osteosarcoma 17/2.8 cell assay. 12 lines were positive (mean, 13.7-fold stimulation, range, 3.0 to 44.0), and 23 lines were negative (mean, 1.2-fold stimulation, range, 0.9 to 1.5). We were successful in establishing five of the positive and six of the negative lines in three to five nude mice per line. Mice implanted with the positive lines uniformly became hypercalcemic (mean serum calcium, 15.8 mg/dl), whereas mice implanted with the negative lines uniformly remained normocalcemic (mean serum calcium, 9.5 mg/dl), in spite of comparable mean tumor size. Acid-urea tumor extracts from each of four hypercalcemic animals contained potent in vitro ACSA (mean, 15.9-fold stimulation), while 5/5 extracts from normocalcemic animals did not (mean, 1.4-fold stimulation). Our study demonstrates that in this model system in vitro ACSA is a reliable predictive marker for HHM in vivo. Whether the protein responsible for this activity is also the mediator of the bone resorption seen in HHM remains to be demonstrated.
背景与目标:
:已提出许多因素作为恶性体液性高钙血症综合征(HHM)的潜在介体,但迄今为止,尚未建立牢固的因果关系。我们试图通过确定培养的肿瘤细胞培养基中腺苷酸环化酶刺激活性(ACSA)的存在与否来预测当这些细胞系在裸鼠体内生长时HHM综合征的发生,从而建立这种关系。在PTH敏感的大鼠骨肉瘤17 / 2.8细胞分析中,对来自35种人肾癌细胞系的条件培养基的ACSA进行了调查。 12线阳性(平均13.7倍刺激,范围3.0至44.0),23线阴性(平均1.2倍刺激,范围0.9至1.5)。我们成功地在每行三到五只裸鼠中建立了五个阳性线和六个阴性线。植入阳性线的小鼠均匀地变成高钙血症(平均血清钙,15.8 mg / dl),而植入阴性线的小鼠均匀地保持正常血钙性(平均血清钙,9.5 mg / dl),尽管平均肿瘤大小相当。来自四只高钙血症动物中每只的酸性尿素肿瘤提取物均含有有效的体外ACSA(平均刺激15.9倍),而来自正常高钙血症动物的5/5提取物则没有(平均1.4倍刺激)。我们的研究表明,在体外该模型系统中,ACSA是体内HHM的可靠预测标记。在HHM中所见,负责这种活性的蛋白质是否也是骨吸收的介体,尚待证实。