Borbath Ivan, Grégoire Vincent, Bergström Mats, Laryea Daniel, Långström Bengt, Pauwels Stanislas
Department of Nuclear Medicine, Catholic University of Louvain, Brussels, Belgium.
Eur J Nucl Med Mol Imaging. 2002 Jan;29(1):19-27. doi: 10.1007/s00259-001-0689-x. Epub 2001 Nov 22.
Uncontrolled cell proliferation is one of the prominent features in cancer development. Precise tools are needed for determination of the proliferation rate before, during and after treatment, thereby permitting assessment of treatment efficacy. The purpose of this study was to validate the use of 5-[(76)Br]bromo-2'-fluoro-2'-deoxyuridine ((76)Br-BFU) as a proliferation marker in an animal tumour model. Comparison was made with 2-[(14)C]thymidine ((14)C-TdR) incorporation and the labelling index assessed by bromodeoxyuridine (BrdUrd-LI). Fibrosarcoma (NFSA)-bearing mice were used for all experiments. Gemcitabine (dFdC), a potent inhibitor of DNA synthesis, was used to modulate cell proliferation. dFdC was injected intraperitoneally at a dose of 0.5 mg/kg or 40 mg/kg to induce partial ( approximately 50%) or complete inhibition of DNA synthesis, respectively. (76)Br-BFU (0.5-3 MBq per animal), (14)C-TdR (37-74 kBq per animal) and cold BrdUrd (60 mg/kg) were injected intraperitoneally in combination or alone. Animals were sacrificed at various times after tracer administration, and tumour and small intestine were removed for determination of radioactivity in whole tissue and the DNA fraction, as well as for LI assessment by flow cytometry. Cimetidine (6 mg/kg) was used to decrease (76)Br-BFU elimination and increase its bioavailability. The fraction of radioactivity associated with DNA increased with the time interval between tracer injection and tissue removal. At 6 h after injection, for both tracers, more than 95% of the radioactivity in the tumours was associated with the DNA fraction and an excellent correlation was observed with the LI. Similar findings were observed in the small intestine. Under all experimental conditions, (76)Br-BFU uptake was 4-10 times lower than (14)C-TdR uptake. Co-injection of cimetidine resulted in a three- to fourfold increase in (76)Br-BFU incorporation without affecting the effect of dFdC on DNA synthesis. (76)Br-BFU is a potentially good tracer for the assessment of tumour proliferation. It has all the specifications required of a PET tracer for clinical use. One limitation to its use is the necessity of co-injecting cimetidine to increase its bioavailability and hence its sensitivity for PET detection.
不受控制的细胞增殖是癌症发展的显著特征之一。在治疗前、治疗期间和治疗后，需要精确的工具来测定增殖率，从而评估治疗效果。本研究的目的是验证5-[(76)Br]溴-2'-氟-2'-脱氧尿苷((76)Br-BFU)作为动物肿瘤模型中增殖标志物的用途。将其与2-[(14)C]胸苷((14)C-TdR)掺入以及通过溴脱氧尿苷评估的标记指数(BrdUrd-LI)进行比较。所有实验均使用荷纤维肉瘤(NFSA)小鼠。吉西他滨(dFdC)是一种有效的DNA合成抑制剂，用于调节细胞增殖。以0.5 mg/kg或40 mg/kg的剂量腹腔注射dFdC，分别诱导部分(约50%)或完全抑制DNA合成。将(76)Br-BFU(每只动物0.5 - 3 MBq)、(14)C-TdR(每只动物37 - 74 kBq)和冷BrdUrd(60 mg/kg)联合或单独腹腔注射。在给予示踪剂后的不同时间点处死动物，取出肿瘤和小肠，用于测定全组织和DNA组分中的放射性，以及通过流式细胞术评估LI。使用西咪替丁(6 mg/kg)来减少(76)Br-BFU的消除并提高其生物利用度。与DNA相关的放射性分数随示踪剂注射与组织取出之间的时间间隔而增加。注射后6小时，对于两种示踪剂，肿瘤中超过95%的放射性与DNA组分相关，并且与LI观察到极好的相关性。在小肠中也观察到类似的结果。在所有实验条件下，(76)Br-BFU的摄取比(14)C-TdR的摄取低4 - 10倍。联合注射西咪替丁导致(76)Br-BFU掺入增加三到四倍，而不影响dFdC对DNA合成的作用。(76)Br-BFU是一种用于评估肿瘤增殖的潜在良好示踪剂。它具有临床使用的PET示踪剂所需的所有特性。其使用的一个限制是需要联合注射西咪替丁以增加其生物利用度，从而提高其对PET检测的敏感性。
