Thiouracil distribution in mice carrying transplantable melanoma.
Thiouracil distribution in mice carrying transplantable melanoma.
复制标题
硫尿嘧啶在携带可移植黑色素瘤的小鼠中的分布。
作者：
R. Fairchild;S. Packer;D. Greenberg;P. Som;A. Brill;I. Fand;W. McNally
其他人发表的数据表明，在痕量剂量的标记TU后，硫尿嘧啶（TU）在黑色素合成期间被选择性摄取。新形成的黑色素中的浓度归因于TU作为黑色素生物合成途径中的“假前体”的掺入。以前提供的信息是各种组织中的相对值，而不是每克组织湿重TU的绝对浓度。后一个参数对于评估辐射吸收剂量以及35 S或14 C标记TU的治疗潜力至关重要。本文描述的实验呈现了TU在BALB/c小鼠的Harding-Passey黑色素瘤和其他正常组织中的绝对摄取。TU浓度与黑色素含量相关，并将结果外推至人黑色素瘤中发现的色素沉着水平。在微量、中等和高剂量（25 µg TU/g体重多次给药）后，测量TU摄取量与时间的函数关系。我们发现肿瘤中[14 C]TU的摄取很高（每克肿瘤占注射剂量的9 - 12%），并且肿瘤与正常组织的浓度比从代谢器官（如肺和肝）的50：1变化到有色全眼的80：1和肌肉和脑等组织的300：1。当给药剂量增加5000倍时，摄取百分比几乎没有变化。在递送的最高剂量TU下，每g肿瘤掺入300 μg TU。在市售[35 S]TU的特定活性下，这将导致约20拉德/小时的剂量，这完全在用于永久性植入治疗的范围内。因此，存在这样的可能性，即原发性和转移性黑素瘤可以在细胞水平上被靶向，并且可以递送细胞毒性剂量，同时将正常组织剂量限制为不大于肿瘤剂量的约2%。TU靶向黑色素瘤类似于碘靶向甲状腺。这种独特的选择性可能允许全身应用放射性标记的TU治疗和诊断黑色素瘤，而不会对正常组织造成不适当的伤害或干扰。
Data published by others have shown that thiouracil (TU) is taken up selectively during melanin synthesis following trace doses of labeled TU. The concentration in newly forming melanin has been attributed to the incorporation of TU as a “false precursor” in the biosynthetic pathway of melanin. Information made available previously has been in terms of relative values in various tissues rather than absolute concentration of TU per g wet weight of tissue. The latter parameter is essential for evaluation of absorbed dose from radiation and thus the therapeutic potential of 35S- or 14C-labeled TU. The experiments described in this paper present the absolute uptake of TU in Harding-Passey melanoma and other normal tissues in BALB/c mice. TU concentration was correlated with melanin content, and results were extrapolated to levels of pigmentation found in human melanoma. Uptake of TU was measured as a function of time following trace, medium, and high doses (multiple doses of 25 µg TU per g body weight). We found that the uptake of [14C]TU in tumor is high (9 to 12% of injected dose per g of tumor) and that tumor:normal tissue concentration ratios varied from 50:1 in metabolizing organs, such as lung and liver, to 80:1 in pigmented whole eye and 300:1 in such tissues as muscle and brain. Little change in the percentage of uptake was noted, as administered dose was increased by 5000 times. At the highest doses of TU delivered, 300 µg TU were incorporated per g tumor. At specific activities of [35S]TU available commercially, this would result in a dose of about 20 rads/hr, which is well within the range used for permanent implant therapy. Thus, the possibility exists that primary and metastatic melanoma can be targeted on a cellular level and that cytotoxic doses can be delivered while limiting normal tissue doses to no greater than about 2% of tumor dose. The targeting of TU to melanoma is analogous to that of iodine to thyroid. This unique selectivity may allow systemic application of radiolabeled TU for therapy and diagnosis of melanoma without undue harm to or interference from normal tissues.