| Budget Amount *help |
¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 1988: ¥300,000 (Direct Cost: ¥300,000)
Fiscal Year 1987: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Research Abstract |
The biochemical basis for synergistic interaction of cytosine arabinoside (Ara-C) and hydroxyurea (HU) or 1-asparaginase (1-Asp) or methotrexate (MTX) was investigated by using human leukemia cell lines. Exposure of cells to HU (lmM) significantly enhanced Ara-CTP (an active metabolite of Ara-C) accumulation in B cell lines, but not in T cell lines. The modulation of Ara-C metabolism by HU occurs at the level of deoxycytidine (CdR) kinase through the regulation of de novo CdR generation, since the changes of dCTP and TTP pools induced by HU, i.e. decrease in dCTP and increase in TTP, were the same in both cell lines. On the contrary, pretreatment of 1-Asp did not have significant effect on Ara-CTP synthesis or incorporation of Ara-C into DNA in either cell line. Next, we showed the synergy between Ara-C and MTX from the point of DNA strand breaks formation. The increase of DNA strand breaks was highly sequence-dependent, since it was demonstrated only when MTX preceded Ara-C. Such was abolished by simultaneous addition of hypoxanthine +thymidine or leucovorin, suggesting the possibility that the primary lesion in DNA was introduced by MTX and that Ara-C inhibited its repair synthesis. Our research overall gave a new insight into the mechanism of synergy between Ara-C and HU/1 Asp/MTX, and was relevant to combination cancer chemotherapy.
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