Maxwell R J, Nielsen F U, Breidahl T, Stødkilde-Jørgensen H, Horsman M R
Gray Laboratory Cancer Research Trust, Northwood, Middx, UK.
Int J Radiat Oncol Biol Phys. 1998 Nov 1;42(4):891-4. doi: 10.1016/s0360-3016(98)00359-9.
Combretastatins have tubulin-binding activity and are being investigated for their toxicity against tumour vasculature. We report the use of 31P and 'H magnetic resonance (MR) spectroscopy and 1H MR imaging for monitoring the effects of combretastatin A-4 prodrug (100mg/kg, i.p.) on energy metabolism and necrosis, respectively, in the C3H murine mammary tumour.
The tumours (volume ca. 200mm3) were grown in the hind foot of mice. MR examinations were performed without anaesthesia within a 7.1 Tesla magnet. 31P MRS (TR = 6 s) was performed before treatment and at 1-, 2-, 3-, and 24-h after injection of drug or saline via an i.p. line. 1H MRS (PRESS; 24microl voxel; TR = 2 s; TE = 135 ms) and both T1-weighted (TR = 0.2 s; TE = 0.02 s) and T2-weighted (TR = 2 s; TE = 0.20 s) 1H MRI were performed before treatment and 2.5 and 24 h afterwards.
The ratio beta-nucleotide triphosphate/inorganic phosphate fell by 33% within 1 h of treatment and remained constant for a further 2 h. A small but significant fall in pH (by 0.11 units) was observed at 1 h. Although an increase in the 1H MR spectroscopy signal at about 1.32 ppm (predominantly from lactate) was observed in some tumours following combretastatin treatment, this effect was not seen consistently. No changes in the intensity of T2-weighted 1H MR images or in tumour necrosis (measured histologically) were detected within 3 h of treatment.
The reduction in tumour energetics and pH was consistent with a reduction in tumour blood flow but this occurred before any significant incidence of haemorrhagic necrosis was detected. The combretastatin dose used to achieve these effects was less than one tenth of the maximum tolerated dose in mice.
康普瑞他汀具有微管蛋白结合活性，目前正在研究其对肿瘤脉管系统的毒性作用。我们报告了使用³¹P和¹H磁共振（MR）波谱以及¹H MR成像，分别监测康普瑞他汀A - 4前药（100mg/kg，腹腔注射）对C3H小鼠乳腺肿瘤能量代谢和坏死的影响。
肿瘤（体积约200mm³）生长于小鼠后足。在7.1特斯拉磁体中，无需麻醉进行MR检查。³¹P MRS（TR = 6 s）在治疗前以及经腹腔注射药物或生理盐水后1、2、3和24小时进行。¹H MRS（PRESS；24微升体素；TR = 2 s；TE = 135 ms）以及T1加权（TR = 0.2 s；TE = 0.02 s）和T2加权（TR = 2 s；TE = 0.20 s）¹H MRI在治疗前以及治疗后2.5和24小时进行。
治疗后1小时内，β - 核苷酸三磷酸/无机磷酸盐的比率下降了33%，并在接下来的2小时内保持恒定。在1小时时观察到pH值有小幅但显著的下降（下降0.11个单位）。虽然在一些接受康普瑞他汀治疗的肿瘤中，在约1.32 ppm处的¹H MR波谱信号增加（主要来自乳酸），但这种效应并不一致。在治疗后3小时内，未检测到T2加权¹H MR图像强度或肿瘤坏死（组织学测量）的变化。
肿瘤能量代谢和pH值的降低与肿瘤血流减少一致，但这发生在检测到任何明显的出血性坏死之前。用于实现这些效应的康普瑞他汀剂量小于小鼠最大耐受剂量的十分之一。
