The Effect of Deazaadenosines on the X-Ray Response of Human Tumor Cell Spheroid

研究了腺苷去氮衍生物对X射线潜在致死损伤(PLDR)修复的影响。照射后1-和7-脱氮腺苷(C^1-和C^7-ADO)可有效抑制平台期HeLa RC-355细胞的PLDR，而3-脱氮腺苷(C^3-ADO)对其修复无影响。C^1-ADO对人骨肉瘤细胞经X射线照射后的多细胞球体的PLDR也有抑制作用。由于已知C^7-ADO在哺乳动物细胞中被磷酸化，而C^3-ADO不被磷酸化，因此我们研究了该通路在PLDR抑制中的意义。检测C^1-ADO对腺苷激酶缺陷型RC-355细胞X射线PLDR的影响。这种药物对变异细胞没有任何影响。结果表明，腺苷激酶的活性对药物的修复抑制作用是必不可少的。进一步研究了脱氮腺苷在对数…和平台p DNA中的细胞代谢。C^1-和C^7-ADO对RC-355细胞的作用更强，分析表明这些药物被代谢成三磷酸盐。随着药物剂量的增加，三磷酸脱氮腺苷的相对比例增加。而正常三磷酸腺苷含量下降，使去氮三磷酸腺苷和三磷酸腺苷总量保持不变。GTP和UTP的池大小在所测试的浓度范围内(10-50 mm)几乎保持不变。这些结果表明，脱氮核苷和脱氮核苷酸是腺苷代谢酶识别的正常底物。然而，已有研究表明，C^1-ADO不被细胞内的腺苷脱氨酶代谢。由于该酶负责各种腺苷类似物的细胞内失活，因此C^1-ADO在组织中有望相对稳定。此外，该药物还具有较高的水溶性和较低的细胞毒性，这使其在临床上使用是可行的。结论：C^1-ADO有望成为提高恶性肿瘤放射治疗效率的临床药物原型。较少

The effects of deaza-derivatives of adenosine on the repair of the X-ray-induced potentially lethal damage (PLDR) were studied. Post-irradiation treatment with 1- and 7-deazaadenosines (C^1- and C^7-Ado) effectively suppressed PLDR in plateau-phase HeLa RC-355 cells, while 3-deazaadenosine (C^3-Ado) had no effect on the repair. C^1-Ado also inhibited PLDR of the X-irradiated multicellular spheroid of human osteosarcoma cells. Since it has been known that C^7-Ado is phosphorylated in mammalian cells while C^3-Ado is not, the significance of the pathway for the PLDR inhibition was studied. The effect of C^1-Ado on X-ray PLDR of the adenosine kinase-deficient variant of RC-355 cells was tested. The drug did not exert any effect on the variant cells. The result indicated that the activity of adenosine kinase is essential for the repair inhibitory effect of the drug. Further cellular metabolism of the deazaadenosines was investigated by HPLC analysis of the nucleotides in log- and plateau-p … More hase RC-355 cells treated with C^1- and C^7-Ado.Analysis showed that these drugs were metabolized into tri-phosphates. Increases in the relative ratios of deazaadenosine triphosphates were observed with increased doses of the drugs. On the other hand, the content of normal ATP was decreased, so that the total amount of deaza-ATP and ATP was constant. The pool size of GTP and UTP remained almost constant within the concentration range tested (10-50 mM). These results suggest that the deazanucleosides and deazanucleotides are recognized as normal substrates by the adenosine-metabolizing enzymes. However, it has been shown that C^1-Ado is not metabolized by cellular adenosine deaminase. Since the enzyme is responsible for the intracellular inactivation of a variety of adenosine analogs, C^1-Ado is expected to be relatively stable in the tissue. In addition, the drug also has properties, such as its high water solubility and the low cytotoxicity, which make it feasible for clinical use. It is concluded that C^1-Ado is a promising candidate for a prototype of a clinical drug which would improve the efficiency of radiation treatment of malignant tumors. Less