DeRubertis F R, Chayoth R, Field J B
J Clin Invest. 1976 Mar;57(3):641-9. doi: 10.1172/JCI108320.
Data from cultured cells have suggested that cyclic AMP and cyclic GMP may be important determinants of cell growth and transformation. However, few studies have examined cyclic nucleotide content and metabolism in naturally occurring tumors of man. Accordingly, in the present study we compared cAMP and cGMP levels and metabolism in carcinomas of the human colon to those of the adjacent uninvolved mucosa after therapeutic resection of these tissues. The cAMP content of the tumors, determined in samples frozen 30 min after excision, was significantly lower than that of the adjacent mucosa, when expressed on the basis of tissue wet weight, protein, or DNA content. By contrast, the cGMP content of the tumors was higher than that of the surrounding mucosa if calculated on the basis of tissue wet weight, but this difference did not persist when correction was made for the higher protein or DNA content of the tumors. Incubation of slices of mucosa or tumor with or without theophylline in vitro increased tissue cAMP and cGMP content above levels observed in frozen samples of the same tissue. However, after such incubations cAMP levels in the tumors remained clearly below that of the mucosa, while cGMP content of the two tissues did not differ. The failure of theophylline to abolish differences in cAMP content and the comparable activities of high and low Km cAMP-phosphodiesterase in homogenates of the two tissues suggested that the lower cAMP content of the tumors was a consequence of diminished cAMP synthesis rather than enhanced degradation. This possibility was supported by the reduction in basal and maximal prostaglandin E1 (PGE1)-responsive adenylate cyclase activity found in tumor homogenates relative to those of mucosa, and the lower levels of cAMP in tumor slices after incubation of the tissues with a maximal dose of PGE1 and theophylline. Since NaF-responsive adenylate cyclase activity was not significantly reduced in the tumors, the lower basal and PGE1 activities may not be related to a deficiency of the catalytic unit of the cyclase complex in this tissue. The role of reduced activity of the adenylate cyclase-cAMP system and/or reduced tissue cAMP-to-cGMP ratios in the pathogenesis of colonic carcinoma is uncertain, but these changes might favor unregulated cellular proliferation.
来自培养细胞的数据表明，环磷酸腺苷（cAMP）和环磷酸鸟苷（cGMP）可能是细胞生长和转化的重要决定因素。然而，很少有研究检测人类自然发生肿瘤中的环核苷酸含量和代谢情况。因此，在本研究中，我们比较了人类结肠癌组织经治疗性切除后，肿瘤组织与相邻未受累黏膜组织中cAMP和cGMP的水平及代谢情况。在切除后30分钟冷冻的样本中测定的肿瘤组织cAMP含量，以组织湿重、蛋白质或DNA含量为基础计算时，显著低于相邻黏膜组织。相比之下，以组织湿重为基础计算时，肿瘤组织的cGMP含量高于周围黏膜组织，但在对肿瘤组织较高的蛋白质或DNA含量进行校正后，这种差异不再存在。在体外将黏膜或肿瘤切片与茶碱一起孵育，或不与茶碱一起孵育，都会使组织cAMP和cGMP含量高于在相同组织的冷冻样本中观察到的水平。然而，经过这样的孵育后，肿瘤组织中的cAMP水平仍明显低于黏膜组织，而两种组织的cGMP含量没有差异。茶碱未能消除cAMP含量的差异，且两种组织匀浆中高Km和低Km的cAMP磷酸二酯酶活性相当，这表明肿瘤组织中较低的cAMP含量是cAMP合成减少而非降解增强的结果。肿瘤匀浆中相对于黏膜组织匀浆，基础和最大前列腺素E1（PGE1）反应性腺苷酸环化酶活性降低，以及在用最大剂量的PGE1和茶碱孵育组织后肿瘤切片中cAMP水平较低，都支持了这种可能性。由于肿瘤组织中NaF反应性腺苷酸环化酶活性没有显著降低，较低的基础和PGE1活性可能与该组织中环化酶复合物催化单位的缺乏无关。腺苷酸环化酶 - cAMP系统活性降低和/或组织中cAMP与cGMP比值降低在结肠癌发病机制中的作用尚不确定，但这些变化可能有利于细胞的无节制增殖。
