1989 Fiscal Year Final Research Report Summary
The Effect of Deazaadenosines on the X-Ray Response of Human Tumor Cell Spheroid
| Project/Area Number |
62480241
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Radiation science
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| Research Institution | Sapporo Medical University |
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Principal Investigator |
MORITA Kazuo Sapporo Medical College, Faculty of Medicine., Professor, 医学部, 教授 (20045347)
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| Co-Investigator(Kenkyū-buntansha) |
OUCHI Atsusi Sapporo Med. Coll., Fac. Med., Instructor, 医学部, 助手 (70168863)
HAREYAMA Masato Sapporo Med. Coll., Fac. Med., Assist. Prof., 医学部, 助手 (10173098)
KUBO Kihei Sapporo Med. Coll., Fac. Med., Instructor, 医学部, 助手 (40117619)
KOIWAI Soichiro Sapporo Med. Coll., Fac. Med., Assist. Prof., 医学部, 講師 (90045336)
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| Project Period (FY) |
1987 – 1989
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| Keywords | Deazaadenosine / Repair of X-ray damages / Potentially lethal damages / Phosphorylation / Multicellular Spheroid / Osteosarcoma / HPLC / Nucleotide Pool |
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| Research Abstract |
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
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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
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