Cohen S M, Ellwein L B, Okamura T, Masui T, Johansson S L, Smith R A, Wehner J M, Khachab M, Chappel C I, Schoenig G P
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha 68198-3135.
Cancer Res. 1991 Apr 1;51(7):1766-77.
Sodium saccharin and sodium ascorbate are known to promote urinary bladder carcinogenesis in rats following initiation with N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) or N-butyl-N-(4-hydroxybutyl) nitrosamine. Sodium salts of other organic acids have also been shown to be bladder tumor promoters. In addition, these substances increase urothelial proliferation in short term assays in rats when fed at high doses. When they have been tested, the acid forms of these salts are without either promoting or cell proliferative inducing activity. The following experiment was designed to compare the tumor promoting activity of various forms of saccharin and to evaluate the role in promotion of urinary sodium, calcium, and pH as well as other factors. Twenty groups of 40 male F344 rats, 5 weeks of age, were fed either FANFT or control diet during a 6-week initiation phase followed by feeding of a test compound for 72 weeks in the second phase. The chemicals were administered to the first 18 groups in Agway Prolab 3200 diet and the last 2 groups were fed NIH-07 diet. The treatments were as follows: (a) FANFT----5% sodium saccharin (NaS); (b) FANFT----3% NaS; (c) FANFT----5.2% calcium saccharin (CaS); (d) FANFT----3.12% CaS; (e) FANFT----4.21% acid saccharin (S); (f) FANFT----2.53% S; (g) FANFT----5% sodium ascorbate; (h) FANFT----4.44% ascorbic acid; (i) FANFT----5% NaS plus 1.15% CaCO3; (j) FANFT----5.2% CaS plus 1.34% NaCl; (k) FANFT----5% NaS plus 1.23% NH4Cl; (l) FANFT----1.15% CaCO3; (m) FANFT----1.34% NaCl; (n) FANFT----control; (o) control----5% NaS; (p) control----5.2% CaS; (q) control----4.21% S; (r) Control----control; (s) FANFT----5% NaS (NIH-07 diet); (t) FANFT----control (NIH-07 diet). NaS, CaS and S without prior FANFT administration were without tumorigenic activity. NaS was found to have tumor promoting activity, showing a positive response at the 5 and 3% dose levels, with significantly greater activity at the higher dose. CaS had slight tumor promoting activity but without a dose response, and S showed no tumor promoting activity. In addition, NaCl showed weak tumor promoting activity, but CaCO3 was without activity. NH4Cl completely inhibited the tumor promoting activity of NaS when concurrently administered with it. NaCl administered with CaS or CaCO3 administered with NaS showed activity similar to that of NaS. Sodium ascorbate was also shown to have tumor promoting activity, with slightly less activity than NaS. Ascorbic acid showed no tumor promoting activity.(ABSTRACT TRUNCATED AT 400 WORDS)
已知糖精钠和抗坏血酸钠在大鼠经N-[4-(5-硝基-2-呋喃基)-2-噻唑基]甲酰胺（FANFT）或N-丁基-N-(4-羟基丁基)亚硝胺启动后可促进膀胱癌发生。其他有机酸盐也已被证明是膀胱肿瘤促进剂。此外，这些物质在高剂量喂食大鼠的短期试验中会增加尿路上皮细胞增殖。当对其进行测试时，这些盐的酸形式既没有促进作用也没有诱导细胞增殖的活性。以下实验旨在比较各种形式糖精的肿瘤促进活性，并评估尿钠、钙、pH值以及其他因素在促进过程中的作用。将20组40只5周龄雄性F344大鼠在6周的启动阶段喂食FANFT或对照饮食，随后在第二阶段喂食测试化合物72周。将化学物质给予前18组的Agway Prolab 3200饮食中，最后2组喂食NIH-07饮食。处理如下：(a) FANFT----5%糖精钠（NaS）；(b) FANFT----3% NaS；(c) FANFT----5.2%糖精钙（CaS）；(d) FANFT----3.12% CaS；(e) FANFT----4.21%酸性糖精（S）；(f) FANFT----2.53% S；(g) FANFT----5%抗坏血酸钠；(h) FANFT----4.44%抗坏血酸；(i) FANFT----5% NaS加1.15%碳酸钙；(j) FANFT----5.2% CaS加1.34%氯化钠；(k) FANFT----5% NaS加1.23%氯化铵；(l) FANFT----1.15%碳酸钙；(m) FANFT----1.34%氯化钠；(n) FANFT----对照；(o)对照----5% NaS；(p)对照----5.2% CaS；(q)对照----4.21% S；(r)对照----对照；(s) FANFT----5% NaS（NIH-07饮食）；(t) FANFT----对照（NIH-07饮食）。未经FANFT预先给药的NaS、CaS和S没有致瘤活性。发现NaS具有肿瘤促进活性，在5%和3%剂量水平显示阳性反应，在较高剂量时活性明显更高。CaS具有轻微的肿瘤促进活性但无剂量反应，S没有肿瘤促进活性。此外，氯化钠显示出较弱的肿瘤促进活性，但碳酸钙没有活性。氯化铵与NaS同时给药时完全抑制了NaS的肿瘤促进活性。与CaS一起给药的氯化钠或与NaS一起给药的碳酸钙显示出与NaS相似的活性。抗坏血酸钠也被证明具有肿瘤促进活性，活性略低于NaS。抗坏血酸没有肿瘤促进活性。（摘要截断于400字）
