Greer S, Schwade J, Marion H S
Department of Microbiology and Immunology, University of Miami School of Medicine, FL 33101, USA.
Int J Radiat Oncol Biol Phys. 1995 Jul 15;32(4):1059-69. doi: 10.1016/0360-3016(94)00596-d.
To extend our findings in previous radiation and biochemical studies with five rodent tumors, in which we used one and occasionally two or three irradiations. The extent of control of the EMT-6 mammary adenocarcinoma was determined using fractionated radiation (12 irradiations) over a 3-week period using the radiosensitizer 5-chloro-2'-deoxycytidine (CldC) and biomodulators of its metabolism: N-(Phosphonacetyl)-L-aspartate (PALA), tetrahydrouridine and 5-fluoro-2'-deoxycytidine (FdC).
Mammary adenocarcinoma EMT-6 tumors implanted 1 week prior to therapy in BALB/c mice were subjected to single daily doses of focused radiation, not exceeding a total of 60 Gy, on days 2-5 of each week. N-(Phosphonacetyl)-L-aspartate (PALA) was administered on the first day of therapy. Five-fluoro-2'-deoxycytidine and CldC were administered in the morning and afternoon, respectively, of the next 2 days, and CldC was administered on the fourth day. Tetrahydrouridine was always coadministered with FdC or CldC. Drug and radiation treatments overlapped for 3 weeks.
Fifty to 80% cures (usually 70%) were obtained with no apparent morbidity and the same moderate weight loss that occurs with radiation alone. Neither tumor regrowth delay nor cures were obtained with drugs or radiation alone. An apparent threefold dose increase effect was obtained with the end point: "days to reach 4 times initial tumor volume." Increasing the radiation dose threefold (without drugs) resulted in four out of five deaths; increasing the dose twofold (without drugs) resulted in extensive weight loss and hair loss in the entire ventral area and no cures. Increasing the dose of drugs or radiation 1.5-fold, in the complete protocol, did not result in increased morbidity. Comparative studies with Iododeoxyuridine demonstrate the heightened efficacy of CldC.
One cannot achieve the same results obtained with CldC and the modulators by merely increasing the dose of radiation. There is a significant window of safety in this approach. The evidence we have obtained with EMT-6, the fifth rodent tumor we have studied with CldC, as well as the demonstrated and proposed reasons for its superior efficacy over 5-Iododeoxyuridine (and 5-Bromodeoxyuridine), drugs in current use, indicate that CldC will allow more aggressive treatment of human tumors with radiation than is now feasible.
扩展我们之前对五种啮齿动物肿瘤进行的放射和生化研究结果，在那些研究中我们使用了一次照射，偶尔也会使用两次或三次照射。使用放射增敏剂5-氯-2'-脱氧胞苷（CldC）及其代谢生物调节剂：N-（膦酰乙酰基）-L-天冬氨酸（PALA）、四氢尿苷和5-氟-2'-脱氧胞苷（FdC），在3周内通过分次照射（12次照射）来确定对EMT-6乳腺腺癌的控制程度。
在BALB/c小鼠中，于治疗前1周植入乳腺腺癌EMT-6肿瘤，在每周的第2至5天接受每日单次聚焦照射，总剂量不超过60 Gy。在治疗的第一天给予N-（膦酰乙酰基）-L-天冬氨酸（PALA）。在接下来2天的上午和下午分别给予5-氟-2'-脱氧胞苷和CldC，第四天给予CldC。四氢尿苷总是与FdC或CldC共同给药。药物和放射治疗重叠3周。
获得了50%至80%的治愈率（通常为70%），且无明显发病情况，体重减轻程度与单纯放疗时相同。单独使用药物或放疗均未获得肿瘤生长延迟或治愈效果。对于“达到初始肿瘤体积4倍所需天数”这一终点，明显有三倍剂量增加效应。将放射剂量增加三倍（不使用药物）导致五分之四的小鼠死亡；将剂量增加两倍（不使用药物）导致整个腹部区域广泛体重减轻和脱毛，且无治愈情况。在完整方案中，将药物或放射剂量增加1.5倍并未导致发病率增加。与碘脱氧尿苷的对比研究表明CldC具有更高的疗效。
仅通过增加放射剂量无法获得与CldC及其调节剂相同的效果。这种方法存在显著的安全窗口。我们用EMT-6（我们研究的第五种使用CldC的啮齿动物肿瘤）获得的证据，以及其比目前使用的药物5-碘脱氧尿苷（和5-溴脱氧尿苷）具有更高疗效的已证实和推测原因，表明CldC将使人类肿瘤的放射治疗比目前可行的方案更具积极性。
