1990 Fiscal Year Final Research Report Summary
Control of Membrane Permeability by External ATP in Animal Cells And its Application to Cancer Chemotherapy
| Project/Area Number |
63571072
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Biological pharmacy
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| Research Institution | 国立予防衛生研究所 |
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Principal Investigator |
KITAGAWA Takayuki Natl. Inst. Hlth, Dept. Chem., Section Chief, 化学部, 化学療法剤室長 (80092188)
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| Co-Investigator(Kenkyū-buntansha) |
AMANO Fumio Natl. Inst. Hlth, Dept. Chem., Chief investigator, 化学部, 主任研究員 (90142132)
AKAMATSU Yuzuru Natl. Inst. Hlth, Dept. Chem. Dept Hand, 化学部, 部長 (00072900)
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| Project Period (FY) |
1988 – 1990
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| Keywords | Membrane permeability / ATP effect / Membrane variant / Calmodulin antagonists / Transformed cells / Cancer chemotherapy / がん化学療法 |
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| Research Abstract |
External ATP causes the passive permeability change in several transformed cells but not in untransformed cells. The mechanism by which external ATP controls the permeability change and possible application of this phenomenon for the in vivo cancer chemotherapy have been examined in this research, and the following results were obtained :
1) The newly synthesized sulfonamide derivatives, which inhibit calmodulin-dependent phosphodiesterase activity, enhanced the ATP-dependent passive permeability change in CHO-K1 cells and B16 melanoma cells. The effective concentrations of these drugs were wider than those of previously known antagonists such as trifluoperazine and W7, suggesting the usefulness of the new drugs for pharmacological use.
2) Modulation of the membrane permeability with external ATP have been made in mildly alkaline Tris-buffered saline. Such increased membrane permeability with the ATP was also observed in B16 melanoma cells at pH 7.4 in a growth medium containing calf ser
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um and divalent ions at normal concentrations. Prolonged exposure of the transformed cells to the ATP in this medium led to cell lysis.
3) Studies on the two ATP-requiring enzyme activities, protein kinase and ATPase, present on the cell surface of CHO-K1 cells demonstrate that these ecto-enzymes are not directly associated with the ATP-dependent permeability change. However, several phosphorylated proteins were detected when the cells were permeabilized by external ATP and these protein phosphorylations were not observed in an ATP-resistant CHO clone. Further characteristics of these phosphoproteins are investigated.
4) Therapeutic effects of antitumor agents such as 5-FU and adriamycin against Ehrlich ascites cells grown in mouse ascites cavity or under the back skin were significantly enhanced by combined treatment with ATP. Similar results were also obtained with B16 melanoma cells. These results indicate the great usefulness of added ATP in the cancer chemotherapy management in vivo. Less
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