Neeman M, Eldar H, Rushkin E, Degani H
Isotope Department, Weizmann Institute of Science, Rehovot, Israel.
Biochim Biophys Acta. 1990 May 2;1052(2):255-63. doi: 10.1016/0167-4889(90)90219-4.
The early changes in the energetics of T47D-clone 11 human breast cancer cells, following treatment with adriamycin and several other anti-cancer drugs were characterized by 31P- and 13C-NMR spectroscopy. Treatment of the cells with cytotoxic doses of either adriamycin (10(-5) M), daunomycin (10(-5) M) or actinomycin-D (2 x 10(-6) M) induced an immediate increase in the content of the nucleoside triphosphate (NTP) pool. A maximum increase of 30 to 50% was reached 6 to 8 h after treatment, and was followed by a gradual decrease, in accord with the decline in cell number due to cell death. High-performance liquid chromatography measurements indicated that the adriamycin-induced build-up of the NTP pool was mainly due to a specific increase in ATP and GTP. Treatment with cytotoxic doses of cytosine arabinofuranoside (10(-4) M) and cis-platin (10(-4) M) and with the antiestrogen tamoxifen at a dose which inhibited growth (2 x 10(-6) M) did not induce an early increase in the NTP content. Adriamycin and actinomycin-D did not alter significantly the rates of glucose consumption and lactate production via glycolysis during the first 4 to 8 h of treatment. Both drug, however, caused during this time interval a 50% inhibition in the rate of glutamate synthesis via the Krebs cycle. Complementary flow cytometry studies have indicated that within 4 h of treatment with either adriamycin or actinomycin-D there is no detectable change in cell cycle distribution. Treatment for longer time periods indicated that each drug affects the cell cycle distribution in a different manner. Thus, the early increase in NTP can not be associated with a specific cell cycle distribution. The results suggest therefore that drugs of the anthracycline and actinomycin type exert a similar specific and early metabolic induction which may affect the energy state of the cells. This induction may relate to the cytotoxic mechanism and could potentially serve as an early marker for response to treatment.
用阿霉素和其他几种抗癌药物处理后，T47D克隆11人乳腺癌细胞能量代谢的早期变化通过31P和13C核磁共振光谱进行了表征。用细胞毒性剂量的阿霉素（10^(-5) M）、柔红霉素（10^(-5) M）或放线菌素-D（2×10^(-6) M）处理细胞后，核苷三磷酸（NTP）池的含量立即增加。处理后6至8小时达到最大增加30%至50%，随后逐渐下降，这与细胞死亡导致的细胞数量减少一致。高效液相色谱测量表明，阿霉素诱导的NTP池积累主要是由于ATP和GTP的特异性增加。用细胞毒性剂量的阿糖胞苷（10^(-4) M）、顺铂（10^(-4) M）以及抑制生长剂量（2×10^(-6) M）的抗雌激素他莫昔芬处理，未诱导NTP含量早期增加。在处理的最初4至8小时内，阿霉素和放线菌素-D并未显著改变通过糖酵解的葡萄糖消耗和乳酸生成速率。然而，在这段时间间隔内，两种药物均导致通过三羧酸循环的谷氨酸合成速率抑制50%。补充的流式细胞术研究表明，用阿霉素或放线菌素-D处理4小时内，细胞周期分布无明显变化。较长时间处理表明，每种药物以不同方式影响细胞周期分布。因此，NTP的早期增加与特定的细胞周期分布无关。结果表明，蒽环类药物和放线菌素类药物具有相似的特异性早期代谢诱导作用，可能影响细胞的能量状态。这种诱导可能与细胞毒性机制有关，并有可能作为治疗反应的早期标志物。
