Palayoor S T, Bump E A, Teicher B A, Coleman C N
Joint Center for Radiation Therapy, Harvard Medical School, Boston, Massachusetts 02215, USA.
Radiat Res. 1997 Aug;148(2):105-14.
Suramin is a novel cytostatic/cytotoxic agent that is currently undergoing clinical trials in the treatment of hormone- and chemo-refractory tumors. Its unusual mechanism of action and its activity against prostate cancer raise the possibility that it could be particularly suitable for combined-modality treatment of prostate cancer. PC3 human prostate cancer cells were used as an in vitro model to test the possible interaction between suramin and ionizing radiation. Treatment with gamma radiation resulted in detachment of PC3 cells from the monolayer, and the detached cells exhibited internucleosomal DNA fragmentation characteristic of apoptosis. Low concentration of suramin (50-100 micrograms/ml, 35-70 microM) increased spontaneous as well as radiation-enhanced apoptosis. However, suramin inhibited spontaneous and radiation-enhanced apoptosis at 300 micrograms/ml (210 microM), a concentration that is more commonly used in the clinic. At this concentration suramin inhibited DNA fragmentation induced by chemotherapeutic drugs as well. The effect of suramin on inhibition of DNA fragmentation was reversible if the suramin was removed 24 h after irradiation. Despite inhibition of radiation-induced apoptosis by 300 micrograms/ml suramin (from 5% to 2.9% at 48 h), clonogenic cell death was enhanced by the combination of suramin and radiation. The effects of radiation and suramin on clonogenic cell survival appeared to be additive by isobologram analysis at clinically relevant radiation doses. Continuous exposure to a lower concentration of suramin (100 micrograms/ml) during the clonogenic assay period was as effective in decreasing clonogenic survival as 48 h exposure to 300 micrograms/ml suramin in decreasing clonogenic survival. Our data indicate that, when used in combination with radiation, suramin may be effective at concentrations that are lower than those required for efficacy as a single agent.
苏拉明是一种新型的细胞生长抑制剂/细胞毒性剂，目前正在进行治疗激素难治性和化疗难治性肿瘤的临床试验。其独特的作用机制以及对前列腺癌的活性表明，它可能特别适合用于前列腺癌的联合治疗。PC3人前列腺癌细胞被用作体外模型，以测试苏拉明与电离辐射之间可能的相互作用。用γ射线照射导致PC3细胞从单层上脱离，脱离的细胞表现出凋亡特有的核小体间DNA片段化。低浓度的苏拉明（50 - 100微克/毫升，35 - 70微摩尔）可增加自发凋亡以及辐射增强的凋亡。然而，苏拉明在300微克/毫升（210微摩尔）时抑制自发凋亡和辐射增强的凋亡，这是临床上更常用的浓度。在此浓度下，苏拉明也抑制化疗药物诱导的DNA片段化。如果在照射后24小时去除苏拉明，其对DNA片段化抑制的作用是可逆的。尽管300微克/毫升的苏拉明抑制辐射诱导的凋亡（48小时时从5%降至2.9%），但苏拉明与辐射联合可增强克隆形成细胞死亡。在临床相关辐射剂量下，通过等效线图分析，辐射和苏拉明对克隆形成细胞存活的影响似乎是相加的。在克隆形成试验期间持续暴露于较低浓度的苏拉明（100微克/毫升）在降低克隆形成存活率方面与48小时暴露于300微克/毫升的苏拉明一样有效。我们的数据表明，与辐射联合使用时，苏拉明可能在低于其作为单一药物发挥疗效所需的浓度下有效。
