Lawrence T S, Davis M A, Maybaum J, Mukhopadhyay S K, Stetson P L, Normolle D P, McKeever P E, Ensminger W D
Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor 48109.
Cancer Res. 1992 Jul 1;52(13):3698-704.
Although the thymidine analogues 5-bromo-2'-deoxyuridine (BrdUrd) and 5-iodo-2'-deoxyuridine (IdUrd) have been used successfully as radiation sensitizers in clinical trials, it is not clear which of these agents is the more promising to pursue. To begin to assess this question with regard to colorectal cancer metastatic to the liver, a study was carried out using HT29 human colon cancer cells in culture and implanted in nude mice as xenografts. Cells and animals were treated with BrdUrd +/- the thymidylate synthase inhibitor 5-fluoro-2'-deoxyuridine (FdUrd), and the results compared to our previous studies with IdUrd +/- FdUrd (T. S. Lawrence, M. A. Davis, P. E. McKeever, J. Maybaum, P. L. Stetson, D. P. Normolle, and W. D. Ensminger. Cancer Res., 51: 3900-3905, 1991). Using cultured cells, it was found that FdUrd (at concentrations of greater than 10 nM) increased: (a) the incorporation of BrdUrd into the DNA of cultured tumor cells; (b) BrdUrd-mediated radiosensitization; (c) BrdUrd-mediated increase in radiation-induced DNA damage; and (d) BrdUrd-mediated decrease in the repair of radiation-induced damage. The incorporation of BrdUrd was greater than or equal to the incorporation of IdUrd previously determined under the same exposure conditions. Studies using nude mice bearing HT29 xenografts showed that FdUrd increased BrdUrd incorporation more into tumors than into the normal liver. Most tumor cells incorporated BrdUrd (labeling index after a 4-day infusion = 87 +/- 2%; SE); in the liver, labeling was confined chiefly to nonparenchymal cells. In both the presence and absence of FdUrd, the incorporation of BrdUrd into tumors was significantly and consistently greater than the incorporation of IdUrd measured under the same conditions of drug administration (by a factor of 1.2-3.6). Furthermore, the administration of BrdUrd +/- FdUrd tended to produce less weight loss and hematological toxicity than IdUrd +/- FdUrd. These findings suggest that BrdUrd may be superior to IdUrd as a radiation sensitizer in the treatment of colorectal cancer metastatic to the liver.
尽管胸苷类似物5-溴-2'-脱氧尿苷（BrdUrd）和5-碘-2'-脱氧尿苷（IdUrd）在临床试验中已成功用作放射增敏剂，但尚不清楚这两种药物中哪一种更具研发前景。为了开始评估关于转移性结直肠癌肝转移的这个问题，我们使用培养的HT29人结肠癌细胞并将其作为异种移植物植入裸鼠体内进行了一项研究。细胞和动物用BrdUrd ± 胸苷酸合成酶抑制剂5-氟-2'-脱氧尿苷（FdUrd）进行处理，并将结果与我们之前用IdUrd ± FdUrd进行的研究（T. S. Lawrence、M. A. Davis、P. E. McKeever、J. Maybaum、P. L. Stetson、D. P. Normolle和W. D. Ensminger。Cancer Res.，51: 3900 - 3905，1991）进行比较。使用培养的细胞发现，FdUrd（浓度大于10 nM）可增加：（a）BrdUrd掺入培养的肿瘤细胞DNA中；（b）BrdUrd介导的放射增敏作用；（c）BrdUrd介导的辐射诱导DNA损伤增加；以及（d）BrdUrd介导的辐射诱导损伤修复减少。在相同暴露条件下，BrdUrd的掺入量大于或等于先前测定的IdUrd的掺入量。使用携带HT29异种移植物的裸鼠进行的研究表明，FdUrd使BrdUrd在肿瘤中的掺入量比在正常肝脏中更多。大多数肿瘤细胞掺入了BrdUrd（4天输注后的标记指数 = 87 ± 2%；标准误）；在肝脏中，标记主要局限于非实质细胞。在有和没有FdUrd的情况下，BrdUrd在肿瘤中的掺入量在相同给药条件下均显著且持续大于IdUrd的掺入量（相差1.2 - 3.6倍）。此外，与IdUrd ± FdUrd相比，给予BrdUrd ± FdUrd导致的体重减轻和血液学毒性往往更小。这些发现表明，在治疗转移性结直肠癌肝转移时，BrdUrd作为放射增敏剂可能优于IdUrd。
