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

脱氮腺苷对人肿瘤细胞球体X射线响应的影响

• 批准号: 62480241
• 负责人: MORITA Kazuo
• 金额: $ 2.82万
• 依托单位: Sapporo Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1987
• 资助国家: 日本
• 起止时间: 1987 至 1989
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-62480241/
• 关键词: Deazaadenosine; Repair of X-ray damages; Potentially lethal damages; Phosphorylation; Multicellular Spheroid; Osteosarcoma; HPLC; Nucleotide Pool; 潜在的致死損傷; アデノシン誘導体; スフェロイド; 放射線感受性; HeLa細胞; 骨肉腫

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

本文研究了腺苷脱氮衍生物对X线诱发的潜在致死性损伤（PLDR）的修复作用。照射后用1-和7-去氮腺苷（C^1-和C^7-Ado）处理可有效抑制平台期HeLa RC-355细胞的PLDR，而3-去氮腺苷（C^3-Ado）对修复无影响。C^1-Ado还抑制X射线照射的人骨肉瘤细胞多细胞球体的PLDR。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，因此研究了该途径对PLDR抑制的意义。检测了C^1-Ado对腺苷激酶缺陷型RC-355细胞X射线PLDR的影响。该药物对变异细胞没有任何作用。结果表明腺苷激酶活性是药物抑制修复作用的必要条件。通过HPLC分析log-和平台-p中的核苷酸，研究脱氮腺苷的进一步细胞代谢。 ...更多信息 用C^1-和C^7-Ado处理RC-355细胞，分析表明这些药物被代谢为三磷酸盐。随着药物剂量的增加，观察到脱氮腺苷三磷酸的相对比率增加。另一方面，正常ATP的含量减少，因此deaza-ATP和ATP的总量是恒定的。GTP和UTP的池大小在测试的浓度范围（10-50 mM）内几乎保持恒定。这些结果表明，deazanucleosides和deazanucleotides被腺苷代谢酶识别为正常底物。然而，已经表明C^1-Ado不被细胞腺苷脱氨酶代谢。由于该酶负责多种腺苷类似物的细胞内失活，因此预期C^1-Ado在组织中相对稳定。此外，该药物还具有高水溶性和低细胞毒性等特性，使其具有临床应用的可行性。结论：C^1-Ado是一种很有前途的候选药物原型，将提高恶性肿瘤的放射治疗效率。少

项目成果

Kubo K.et al.: "The Effects of Deazaderivatives of Adenosine on the Repair of the Potentially Lethal Damage in X-Irradiated HeLa Cells" 投稿中.

Kubo K. 等人：“腺苷脱氮衍生物对修复 X ​​射线照射的 HeLa 细胞潜在致命损伤的影响”正在进行中。

Kubo K.et al.: "Establishment of Cell Lines from Human Osteosarcoma" Proc.Japan Acad. 64B. 233-236 (1988)

Kubo K.等人：“人骨肉瘤细胞系的建立”Proc.Japan Acad。

Kubo K.et al.: "Establishment of Cell Lines from Human Osteosarcoma" Proc.Japan Acad.64B. 233-236 (1988)

Kubo K.等人：“人骨肉瘤细胞系的建立”Proc.Japan Acad.64B。

大久保整 久保喜平: "デアザアデノシンによるX線潜在的致死損傷修復阻害の作用機序に関する研究" 札幌医学雑誌. 59. 13-24 (1990)

Osamu Okubo 和 Kihei Kubo：“脱氮腺苷抑制潜在致命 X 射线损伤修复的作用机制研究”札幌医学杂志 59. 13-24 (1990)。

KUBO,K.,et al.: Proc.Japan Acad.64(B). 233-236 (1988)

KUBO,K. 等人：Proc.Japan Acad.64(B)。