Greer S, Santos O, Gottlieb C, Schwade J, Marion H S
Department of Microbiology and Immunology, University of Miami School of Medicine, FL 33136.
Int J Radiat Oncol Biol Phys. 1992;22(3):505-10. doi: 10.1016/0360-3016(92)90863-d.
5-Chlorodeoxycytidine (CldC), coadministered with modulators of pyrimidine metabolism, is an effective radiosensitizer of murine tumors. Past studies that utilized RIF-1 tumors in C3H mice and Lewis lung carcinoma (LLC) in BDF1 mice have been extended with an emphasis on using multiple cycles of drug administration followed by irradiation of LLC and the use of two additional tumor models. Four of seven cures of BDF1 mice bearing LLC were obtained with three doses of 20 Gy irradiation, in which the first and third dose were preceded by a "Standard Protocol" that includes N-(phosphonacetyl)-L-aspartic acid (PALA), 5-fluorodeoxycytidine (FdC), tetrahydrouridine, and the radiosensitizer, 5-chlorodeoxycytidine. No cures were obtained in groups of mice receiving radiation alone or drugs alone, and there were no "no takes" in untreated control groups (six mice/group). Extensive tumor inhibition, exceeding that obtained with drugs or radiation alone, was obtained with two cycles of drugs and radiation combined when a dimethybenzanthracene-induced mammary adenocarcinoma was used in BALB/c mice. With the EMT-6 tumor in BALB/c mice, doses of 10 and 20 Gy were administered 9 and 16 days after tumor implantation, each preceded with the Standard Protocol; this resulted in a tumor growth delay of 24 days. No tumor growth delay occurred with drugs or radiation alone. The omission of PALA, FdC or CldC from the Standard Protocol resulted in loss of tumor control, which was obtained with the complete protocol. The fact that 5-chlorodeoxycytidine is an effective radiosensitizer in four rodent tumor systems is compelling evidence that it has potential as a radiosensitizer of human tumors, especially in view of its tumor selectivity and its resistance to catabolism when used with modulators of its metabolism, and in view of the high levels of the key enzymes in human tumors, which can convert 5-chlorodeoxycytidine to 5-chlorodeoxyuridine triphosphate, the proximate radiosensitizer.
5-氯脱氧胞苷（CldC）与嘧啶代谢调节剂联合使用时，是一种有效的小鼠肿瘤放射增敏剂。过去利用C3H小鼠的RIF-1肿瘤和BDF1小鼠的Lewis肺癌（LLC）进行的研究得到了扩展，重点是使用多个周期的药物给药，随后对LLC进行照射，并使用另外两种肿瘤模型。携带LLC的BDF1小鼠中有七只治愈了四只，采用了三剂20 Gy的照射，其中第一剂和第三剂之前采用了“标准方案”，该方案包括N-（膦酰乙酰基）-L-天冬氨酸（PALA）、5-氟脱氧胞苷（FdC）、四氢尿苷和放射增敏剂5-氯脱氧胞苷。单独接受辐射或单独接受药物治疗的小鼠组均未治愈，未治疗的对照组（每组六只小鼠）也没有“未长出肿瘤”的情况。当在BALB/c小鼠中使用二甲基苯并蒽诱导的乳腺腺癌时，联合使用两个周期的药物和辐射可获得广泛的肿瘤抑制，其抑制程度超过单独使用药物或辐射。对于BALB/c小鼠中的EMT-6肿瘤，在肿瘤植入后第9天和第16天分别给予10和20 Gy的剂量，每次之前均采用标准方案；这导致肿瘤生长延迟24天。单独使用药物或辐射均未出现肿瘤生长延迟。从标准方案中省略PALA、FdC或CldC会导致失去肿瘤控制，而完整方案则可实现肿瘤控制。5-氯脱氧胞苷在四种啮齿动物肿瘤系统中是一种有效的放射增敏剂，这一事实有力地证明了它有潜力成为人类肿瘤的放射增敏剂，特别是考虑到它的肿瘤选择性以及与代谢调节剂联合使用时对分解代谢的抗性，还考虑到人类肿瘤中关键酶的高水平，这些酶可将5-氯脱氧胞苷转化为5-氯脱氧尿苷三磷酸，即直接的放射增敏剂。
