Meurling Lennart, Márquez Marcela, Nilsson Sten, Holmberg Anders R
Department of Oncology, Karolinska Institute, SE-171 76 Stockholm, Sweden.
Int J Oncol. 2009 Aug;35(2):281-5.
Guanidine compounds have important biochemical properties. Aminoguanidine, as an example, is an anti-oxidant, a nitric oxide synthase inhibitor (NOS) which prevents nitric oxide formation, and an inhibitor of advanced glycosylation end products (AGEs). As an anti-oxidant, aminoguanidine may affect the formation of atherosclerotic lesions through protection from LDL oxidation. Inhibition of AGEs could have a preventive effect on the tissue damage caused by diabetes where AGEs are considered to be an important factor. The role of NO in cancer is complex and not fully understood, but it may have influence on growth and progression. In this study, the tumor growth inhibitory effect of conjugated guanidine (i.e. a polyguanidine) was investigated. The effect on tumor cell growth was studied in cultures of prostate, breast, bladder and renal cell cancer, and a fluorometric cytotoxicity assay was performed. Guanidine conjugates were prepared by reacting aminoguanidine or agmatine with periodate oxidized dextran followed by reductive amination. The cytotoxic effect was compared with an anthracycline (adriamycin). The dextran-guanidine conjugates were cytotoxic at low micromolar concentrations, and the dextran-aminoguanidine conjugate (GDC) had the highest efficacy, being more efficient than adriamycin, in all of the tested tumor cell lines. Breast and prostate cancer cells were the most sensitive. At 0.5 microM, GDC killed >95% of the breast cancer cells compared to 25% for Adriamycine. In prostate cancer cells, GDC killed approximately 55% of the cells at 0.1 microM and 100% of the cells at 0.5 microM compared to approximately 22 and approximately 62%, respectively, for adriamycin. Unconjugated aminoguanidine and agmatine did not seem to affect tumor cell growth even at high concentrations (mM). Polymer- conjugated guanidine is a potentially useful template for the construction of therapeutic tumor targeting cytotoxic agents.
胍类化合物具有重要的生化特性。例如，氨基胍是一种抗氧化剂，一种可防止一氧化氮形成的一氧化氮合酶抑制剂（NOS），也是晚期糖基化终产物（AGEs）的抑制剂。作为一种抗氧化剂，氨基胍可通过保护低密度脂蛋白免受氧化来影响动脉粥样硬化病变的形成。抑制AGEs可能对糖尿病所致的组织损伤具有预防作用，因为AGEs被认为是一个重要因素。一氧化氮在癌症中的作用很复杂且尚未完全明确，但它可能对肿瘤生长和进展产生影响。在本研究中，研究了共轭胍（即聚胍）的肿瘤生长抑制作用。在前列腺癌、乳腺癌、膀胱癌和肾细胞癌培养物中研究了其对肿瘤细胞生长的影响，并进行了荧光细胞毒性测定。通过使氨基胍或胍丁胺与高碘酸盐氧化的葡聚糖反应，随后进行还原胺化反应来制备胍共轭物。将细胞毒性作用与一种蒽环类药物（阿霉素）进行比较。葡聚糖 - 胍共轭物在低微摩尔浓度下具有细胞毒性，葡聚糖 - 氨基胍共轭物（GDC）在所有测试的肿瘤细胞系中具有最高的效力，比阿霉素更有效。乳腺癌和前列腺癌细胞最为敏感。在0.5微摩尔浓度下，GDC杀死了>95%的乳腺癌细胞，而阿霉素杀死的细胞为25%。在前列腺癌细胞中，GDC在0.1微摩尔浓度下杀死了约55%的细胞，在0.5微摩尔浓度下杀死了100%的细胞，相比之下，阿霉素分别杀死了约22%和约62%的细胞。即使在高浓度（毫摩尔）下，未共轭的氨基胍和胍丁胺似乎也不影响肿瘤细胞生长。聚合物共轭胍是构建治疗性肿瘤靶向细胞毒性药物的潜在有用模板。
