Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104-6069, USA.
NMR Biomed. 2013 Jan;26(1):98-105. doi: 10.1002/nbm.2824. Epub 2012 Jun 29.
In vivo (31) P MRS demonstrates that human melanoma xenografts in immunosuppressed mice treated with lonidamine (LND, 100 mg/kg intraperitoneally) exhibit a decrease in intracellular pH (pH(i) ) from 6.90 ± 0.05 to 6.33 ± 0.10 (p < 0.001), a slight decrease in extracellular pH (pH(e) ) from 7.00 ± 0.04 to 6.80 ± 0.07 (p > 0.05) and a monotonic decline in bioenergetics (nucleoside triphosphate/inorganic phosphate) of 66.8 ± 5.7% (p < 0.001) relative to the baseline level. Both bioenergetics and pH(i) decreases were sustained for at least 3 h following LND treatment. Liver exhibited a transient intracellular acidification by 0.2 ± 0.1 pH units (p > 0.05) at 20 min post-LND, with no significant change in pH(e) and a small transient decrease in bioenergetics (32.9 ± 10.6%, p > 0.05) at 40 min post-LND. No changes in pH(i) or adenosine triphosphate/inorganic phosphate were detected in the brain (pH(i) , bioenergetics; p > 0.1) or skeletal muscle (pH(i) , pH(e) , bioenergetics; p > 0.1) for at least 120 min post-LND. Steady-state tumor lactate monitored by (1) H MRS with a selective multiquantum pulse sequence with Hadamard localization increased approximately three-fold (p = 0.009). Treatment with LND increased the systemic melanoma response to melphalan (LPAM; 7.5 mg/kg intravenously), producing a growth delay of 19.9 ± 2.0 days (tumor doubling time, 6.15 ± 0.31 days; log(10) cell kill, 0.975 ± 0.110; cell kill, 89.4 ± 2.2%) compared with LND alone of 1.1 ± 0.1 days and LPAM alone of 4.0 ± 0.0 days. The study demonstrates that the effects of LND on tumor pH(i) and bioenergetics may sensitize melanoma to pH-dependent therapeutics, such as chemotherapy with alkylating agents or hyperthermia.
在体（31）P MRS 研究表明，在免疫抑制的荷黑色素瘤小鼠中，用 Lonidamine（LND，100mg/kg 腹腔内注射）治疗后，细胞内 pH（pH（i））从 6.90±0.05 降至 6.33±0.10（p<0.001），细胞外 pH（pH（e））略有下降从 7.00±0.04 降至 6.80±0.07（p>0.05），核苷三磷酸/无机磷酸盐的生物能量（bioenergetics）下降了 66.8±5.7%（p<0.001）与基线水平相比。LND 治疗后至少 3 小时，生物能量和 pH（i）均持续下降。在 LND 治疗后 20 分钟，肝脏出现短暂的细胞内酸化，pH（i）降低 0.2±0.1 个单位（p>0.05），细胞外 pH（e）无明显变化，生物能量短暂下降（32.9±10.6%，p>0.05）在 LND 治疗后 40 分钟。LND 治疗后至少 120 分钟，在大脑（pH（i），生物能量；p>0.1）或骨骼肌（pH（i），pH（e），生物能量；p>0.1）中未检测到 pH（i）或三磷酸腺苷/无机磷酸盐的变化。用（1）H MRS 监测稳态肿瘤乳酸，使用选择性多量子脉冲序列和 Hadamard 定位，增加了约三倍（p=0.009）。用 LND 治疗增加了黑色素瘤对美法仑（LPAM；7.5mg/kg 静脉注射）的全身反应，导致肿瘤生长延迟 19.9±2.0 天（肿瘤倍增时间，6.15±0.31 天；对数（10）细胞杀伤率，0.975±0.110；细胞杀伤率，89.4±2.2%）与 LND 单独治疗的 1.1±0.1 天和 LPAM 单独治疗的 4.0±0.0 天相比。研究表明，LND 对肿瘤 pH（i）和生物能量的影响可能使黑色素瘤对 pH 依赖性治疗药物（如烷化剂化疗或热疗）敏感。
