van Waarde Aren, Been Lukas B, Ishiwata Kiichi, Dierckx Rudi A, Elsinga Philip H
Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
J Nucl Med. 2006 Sep;47(9):1538-45.
The significant presence of nontumor cell populations within tumors can complicate the assessment of in vivo tumor metabolism during therapy. To more clearly define the impact of cytotoxic agents, we compared early changes in the uptake of 6 PET tracers in cultured glioma cells. Doxorubicin (1 micromol/L), cisplatin (10 micromol/L), and 5-fluorouracil (10 mmol/L) were selected to target different aspects of cellular metabolism.
The tracers were 2 extracellular sigma-receptor ligands, (18)F-FE-SA5845 (nonsubtype selective) and (11)C-SA4503 (sigma-1), the nucleoside 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT), (11)C-choline, (11)C-methionine, and (18)F-FDG. C6 glioma cells were grown as monolayers and exposed to cytotoxic agents at concentrations at least 1 order of magnitude higher than the concentration for 50% growth inhibition of this cell line. Effects on cellular parameters were measured after 0, 1, 2, 3, 4, and 24 h.
All treatments resulted in a decline in cell numbers within 24 h. The binding of the sigma-ligands (11)C-SA4503 and (18)F-FE-SA5845 and the uptake of (11)C-choline (normalized for the number of viable cells) were strongly increased. The uptake of (18)F-FDG showed little change, and cellular accumulation of (18)F-FLT and (11)C-methionine was decreased. Uptake of (18)F-FLT and (11)C-methionine was related to the fraction of cells in S-phase, but not under all conditions: (a) doxorubicin caused a more rapid decline in (18)F-FLT uptake than in the S-phase fraction because of depletion of cellular adenosine triphosphate, and (b) cisplatin inhibited the transport of (11)C-methionine across the tumor cell membrane.
Increased binding of sigma-ligands and an increased uptake of (11)C-choline after chemotherapy may reflect active membrane repair in damaged cells. (18)F-FLT and (11)C-methionine behaved as proliferation markers. However, the accumulation of (18)F-FDG reflected not the proliferation rate but, rather, the number of viable cells per well.
肿瘤内非肿瘤细胞群体的大量存在会使治疗期间体内肿瘤代谢的评估变得复杂。为了更清楚地确定细胞毒性药物的影响，我们比较了6种正电子发射断层扫描（PET）示踪剂在培养的胶质瘤细胞中的早期摄取变化。选择阿霉素（1微摩尔/升）、顺铂（10微摩尔/升）和5-氟尿嘧啶（10毫摩尔/升）来靶向细胞代谢的不同方面。
示踪剂包括2种细胞外σ受体配体，（18）F-FE-SA5845（非亚型选择性）和（11）C-SA4503（σ-1），核苷3'-脱氧-3'-（18）F-氟胸苷（（18）F-FLT）、（11）C-胆碱、（11）C-蛋氨酸和（18）F-氟代脱氧葡萄糖（（18）F-FDG）。C6胶质瘤细胞单层生长，并暴露于浓度至少比该细胞系50%生长抑制浓度高1个数量级的细胞毒性药物中。在0、1、2、3、4和24小时后测量对细胞参数的影响。
所有处理均导致24小时内细胞数量下降。σ配体（11）C-SA4503和（18）F-FE-SA5845的结合以及（11）C-胆碱的摄取（根据活细胞数量进行归一化）显著增加。（18）F-FDG的摄取变化不大，（18）F-FLT和（11）C-蛋氨酸的细胞内积累减少。（18）F-FLT和（11）C-蛋氨酸的摄取与S期细胞分数有关，但并非在所有情况下都是如此：（a）由于细胞三磷酸腺苷的消耗，阿霉素导致（18）F-FLT摄取的下降比S期分数的下降更快；（b）顺铂抑制（11）C-蛋氨酸跨肿瘤细胞膜的转运。
化疗后σ配体结合增加和（11）C-胆碱摄取增加可能反映受损细胞的主动膜修复。（18）F-FLT和（11）C-蛋氨酸表现为增殖标志物。然而，（18）F-FDG的积累反映的不是增殖率，而是每孔活细胞的数量。
