| Budget Amount *help |
¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1995: ¥400,000 (Direct Cost: ¥400,000)
Fiscal Year 1994: ¥600,000 (Direct Cost: ¥600,000)
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| Research Abstract |
It has been established that acidic intracellular environment enhances the thermosensitivity of tumor cells. The effect of melphalan in combination with mild hyperthermia on mice tumor was investigated both in vitro and in vivo, and the influence of acidity on the thermal enhancement of the cytotoxicity of melphalan (mel) was also investigated. FSA-II tumor was transplanted S.C.in the thigh of C3H mice and when the tumor grew to about 200mm3, mice were intra-peritoneally injected with various doses of melphalan and the tumors were heated by immersing into a 42.5 C water bath for 1 hr. The volume of untreated tumors increased 4 times in 6 days. Both heating alone and injection on 5 mg/kg of mel delayd the growth about 2 days. The tumor growth was markedly suppressed in groups combined mel and mild heating. The growth was delayd 6days, 12days and 20days at mel 2.5mg/kg, 5mg/kg and 10mg/kg with heat respectively. The decline in clonogenic cell number in tumor was far more pronounced when
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the tumors were treated with hyperthermia in combination with mel than with either treatment alone. In vitro studies also indicated that heating markedly increased the cytotoxicity of mel and that mel is significantly more toxic in acidic medium than neutral medium. HMA is an analog of amiloride. The intracellular pH (pHi) was detected with BCECF fluorescence spectroscopy method. The difference between the pHi in the presence of 10uM HMA and absence of HMA was significant.
10mg/kg of HMA was injected through the tail vein 20 minutes before heating. The effect of HMA plus heat group was simillar to that of heat alone. However, when treated with 10mg/kg HMA together with 2.5 mg/kg mel and the tumor was heated, the tumor growth delay was longer than 15days, which was almost the same tumor suppression effect that caused by 7.5 mg/kg mel and heating. In this group 30% of tumors were cured, which is the same effect in group received 7.5mg/kg or more of mel and heated. Conclusion : The effect of mel to suppress the tumor growth was markedly potentiated by mild hyperthermia. The anti-tumor effect of melphalan with mild hyperthermis was further enhanced by HMA,which lowers the intracellular pH. Less
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