Chen T B, Bajzer Z, Macura S, Vuk-Pavlovic S
Department of Oncology, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA.
NMR Biomed. 1999 May;12(3):157-67. doi: 10.1002/(sici)1099-1492(199905)12:3<157::aid-nbm551>3.0.co;2-i.
Glucosamine (GlcN) modulates fluoropyrimidine metabolism and enhances cytotoxicity of 5-fluorouridine (FUrd), but not of 5-fluorouracil (FUra), in human tumor models. To elucidate the underlying metabolic differences between FUra and FUrd, by the use of 19F and 31P NMR spectroscopy we studied these drugs in multicell tumor spheroids (MTS) formed by human colon carcinoma cells HT-29. This experimental system allowed detailed kinetic measurements of anabolic intracellular phosphates and fluorophosphates over periods of up to 2 days. Time-dependent NMR data were reduced and interpreted by the use of nonlinear compartmental models which yielded numerical values for the empirical rate constants characterizing mass transfer among the compartments. An analysis of these rate constants indicated qualitative and quantitative differences in the metabolism of FUra and FUrd and in the effects of GlcN on these drugs. The enhanced generation of FUDP-hexoses was a predicted effect of GlcN, but inhibited formation of fluorouridine diphosphates and fluorouridine triphosphates in FUra-treated MTS, and the magnitude of stimulation of fluoropyrimidine incorporation into macromolecules in FUrd-treated MTS were not predicted.
在人类肿瘤模型中，氨基葡萄糖（GlcN）可调节氟嘧啶代谢并增强5-氟尿苷（FUrd）的细胞毒性，但对5-氟尿嘧啶（FUra）无效。为阐明FUra和FUrd潜在的代谢差异，我们利用19F和31P核磁共振波谱技术，对人结肠癌细胞HT-29形成的多细胞肿瘤球体（MTS）中的这些药物进行了研究。该实验系统能够在长达2天的时间内，对合成代谢的细胞内磷酸盐和氟磷酸盐进行详细的动力学测量。利用非线性房室模型对随时间变化的核磁共振数据进行简化和解释，该模型可得出表征各房室间质量转移的经验速率常数的数值。对这些速率常数的分析表明，FUra和FUrd的代谢以及GlcN对这些药物的影响在定性和定量方面均存在差异。GlcN可促进FUDP-己糖的生成，这是预期的效果，但在FUra处理的MTS中，氟尿苷二磷酸和氟尿苷三磷酸的形成受到抑制，而且在FUrd处理的MTS中，氟嘧啶掺入大分子的刺激程度也未在预期之内。
