Verma A K, Ertürk E, Bryan G T
Cancer Res. 1983 Dec;43(12 Pt 1):5964-71.
The effects of intraurethral or i.p. administration of a mouse skin tumor promoter phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), on rodent urinary bladder transitional epithelium were studied. TPA, when instilled into the urinary bladder of inbred rats (female Fischer, F344) or mice (C3H, ICR, C57BL X DBA/2 F1) at a dose as low as 0.16 nmol, led to a significant (about 10-fold) increase in bladder ornithine decarboxylase (EC 4.1.1.17) (ODC) activity. Peak ODC activity was observed at about 6 hr, and enzyme activity returned to base levels about 14 hr after intravesical TPA. Administration of TPA i.p. in dimethyl sulfoxide also induced vesical ODC at 4 hr after treatment. The magnitude of vesical ODC induction correlated well with the ability of a series of phorbol esters to promote mouse skin tumor formation (TPA greater than phorbol didecanoate greater than phorbol dibenzoate, and phorbol diacetate or phorbol did not induce bladder ODC activity). Mezerein, a second stage mouse skin tumor promoter, induced urinary bladder ODC as much as TPA did. Increased ODC activity by TPA was the result of an increased amount of ODC protein localized mostly (greater than 60%) in urinary bladder mucosa. Intraurethrally administered TPA induced transitional cell hyperplasia starting at Day 2, and it persisted for about 7 days. The urothelium regained normal histology 13 days after TPA treatment. TPA bound specifically and with high affinity to murine bladder mucosa and muscularis particulate preparations. Scatchard analysis of mucosal binding revealed a Kd of 0.82 nM; at saturation, 2.43 pmol were bound per mg protein. Since TPA binds specifically to urinary bladder epithelium, and the induction of ODC activity is one of the properties of tumor promoters, one may conclude that TPA may promote urinary bladder carcinogenesis. Intravesical saccharin also induced urinary bladder ODC activity, but TPA at equimolar quantity was far more potent than saccharin. Thus TPA, being a structurally well-defined molecule, may be a useful compound to study the phenomenon of the tumor promotion stage in urinary bladder carcinogenesis.
研究了尿道内或腹腔注射小鼠皮肤肿瘤促进剂佛波酯12 - O - 十四烷酰佛波醇 - 13 - 乙酸酯（TPA）对啮齿动物膀胱移行上皮的影响。当以低至0.16 nmol的剂量将TPA注入近交系大鼠（雌性Fischer，F344）或小鼠（C3H、ICR、C57BL×DBA/2 F1）的膀胱时，可导致膀胱鸟氨酸脱羧酶（EC 4.1.1.17）（ODC）活性显著增加（约10倍）。ODC活性在约6小时达到峰值，膀胱内注射TPA后约14小时酶活性恢复至基础水平。腹腔注射溶于二甲基亚砜的TPA在处理后4小时也诱导膀胱ODC。膀胱ODC诱导的程度与一系列佛波酯促进小鼠皮肤肿瘤形成的能力密切相关（TPA＞佛波二癸酸酯＞佛波二苯甲酸酯，而佛波二乙酸酯或佛波未诱导膀胱ODC活性）。第二阶段小鼠皮肤肿瘤促进剂美泽瑞因诱导膀胱ODC的程度与TPA相同。TPA使ODC活性增加是由于ODC蛋白量增加，其主要定位于膀胱黏膜（＞60%）。尿道内注射TPA从第2天开始诱导移行细胞增生，并持续约7天。TPA处理13天后尿路上皮恢复正常组织学。TPA与小鼠膀胱黏膜和肌层微粒体制剂特异性且高亲和力结合。黏膜结合的Scatchard分析显示解离常数（Kd）为0.82 nM；饱和时，每毫克蛋白结合2.43 pmol。由于TPA特异性结合膀胱上皮，且ODC活性诱导是肿瘤促进剂的特性之一，因此可以得出结论，TPA可能促进膀胱癌发生。膀胱内注入糖精也诱导膀胱ODC活性，但等摩尔量的TPA比糖精的作用强得多。因此，TPA作为一种结构明确的分子，可能是研究膀胱癌发生中肿瘤促进阶段现象的有用化合物。
