Heston W D, Yang C R, Pliner L, Russo P, Covey D F
Cancer Res. 1987 Jul 15;47(14):3627-31.
We have previously demonstrated that prostate and prostate-derived rodent tumors can be manipulated into increasing their accumulation of radiolabeled putrescine by alpha-difluoromethylornithine (DFMO)-induced depletion of intracellular putrescine and spermidine. As methods which increase intracellular accumulation of cytotoxic agents often increase the chemotherapeutic effectiveness of the agent, we examined whether an alkylating derivative of putrescine would be cytotoxic to tumor cells. We present here our findings on the cytotoxicity of the aziridinyl derivative of putrescine (AZP) against prostatic cancer cells. The apparent Km for putrescine was 2.5 microM with or without DFMO pretreatment and the apparent Ki for AZP was 1 microM with or without DFMO pretreatment. Intracellular polyamine depletion by DFMO pretreatment resulted in a 3.7-fold greater accumulation of AZP compared to non-DFMO-treated cells. The growth inhibitory activity of AZP was increased with prior polyamine depletion by DFMO with the 50% effective dose decreasing from 18 microM to 2.1 microM. Putrescine was able to block the cytotoxic effect of AZP. Putrescine was also able to rescue the AZP-treated PC-3 cells for up to 6 h following a 1-h exposure to AZP. It appears that aziridinylputrescine behaves like putrescine in that it competes with putrescine for uptake into the cell and, like putrescine, has its uptake into the cell increased by prior polyamine depletion. It differs from putrescine in that it expresses cytotoxic activity and inhibits the growth of the human prostate-derived PC-3 cell line. This cytotoxic activity is also increased by prior polyamine depletion. The cytotoxic behavior of AZP is dependent both on the concentration and duration of exposure. Putrescine can rescue the cells from the effect of AZP. AZP is a potentially useful cytotoxic analogue that utilizes the polyamine transport system for its uptake into the cell.
我们之前已经证明，通过α-二氟甲基鸟氨酸（DFMO）诱导细胞内腐胺和亚精胺耗竭，可以使前列腺及源自前列腺的啮齿动物肿瘤增加其对放射性标记腐胺的摄取。由于增加细胞内细胞毒性药物蓄积的方法通常会提高该药物的化疗效果，我们研究了腐胺的一种烷基化衍生物是否对肿瘤细胞具有细胞毒性。在此，我们展示了腐胺氮丙啶衍生物（AZP）对前列腺癌细胞的细胞毒性研究结果。无论有无DFMO预处理，腐胺的表观米氏常数（Km）均为2.5微摩尔，AZP的表观抑制常数（Ki）无论有无DFMO预处理均为1微摩尔。与未用DFMO处理的细胞相比，DFMO预处理导致细胞内多胺耗竭，使AZP的蓄积增加了3.7倍。DFMO预先耗竭多胺后，AZP的生长抑制活性增强，半数有效剂量从18微摩尔降至2.1微摩尔。腐胺能够阻断AZP的细胞毒性作用。在暴露于AZP 1小时后，腐胺还能够拯救经AZP处理的PC-3细胞长达6小时。氮丙啶腐胺的行为似乎与腐胺相似，即它与腐胺竞争进入细胞，并且与腐胺一样，预先耗竭多胺会使其进入细胞的量增加。它与腐胺的不同之处在于它表现出细胞毒性活性并抑制源自人前列腺的PC-3细胞系的生长。预先耗竭多胺也会增强这种细胞毒性活性。AZP的细胞毒性行为取决于暴露的浓度和持续时间。腐胺可以使细胞免受AZP的影响。AZP是一种潜在有用的细胞毒性类似物，它利用多胺转运系统进入细胞。
