Yamazaki H, Dilworth A, Myers C E, Sinha B K
Biochemical & Molecular Pharmacology Section, National Cancer Institute, NIH, Bethesda, MD 20892.
Prostate. 1993;23(1):25-36. doi: 10.1002/pros.2990230104.
Suramin, a highly sulfonated drug, has been reported to be effective against several human malignancies in vitro and in vivo, and currently is undergoing clinical trials against prostate tumors. The biochemical and molecular mechanisms for suramin's antiproliferative activity are not clear. In order to define the biochemical basis for its antitumor activity and to enhance suramin's chemotherapeutic potential while decreasing its toxicity, we have examined interactions of suramin with topoisomerase I and II and several clinically active anticancer drugs against the human prostate (PC3 and LNCaP) cancer cell line. While etoposide, m-AMSA, camptothecin, and SN-38 (the active metabolite of CPT-11) were active in killing prostate cells as single agents, combinations of suramin and these agents were antagonistic against these cells. We found that suramin inhibited activities of purified topoisomerase I and II in vitro as measured by relaxation and cleavage assays. Further studies indicated that suramin also inhibited the drug-induced DNA damage in vitro and in isolated nuclei. These findings indicate that combinations of suramin with topoisomerase inhibitors, for example, VP-16, m-AMSA, or CPT, may not be beneficial to patients receiving suramin-containing chemotherapy.
苏拉明是一种高度磺化的药物，据报道它在体外和体内对多种人类恶性肿瘤有效，目前正在进行针对前列腺肿瘤的临床试验。苏拉明抗增殖活性的生化和分子机制尚不清楚。为了确定其抗肿瘤活性的生化基础，并在降低毒性的同时增强苏拉明的化疗潜力，我们研究了苏拉明与拓扑异构酶I和II以及几种针对人前列腺（PC3和LNCaP）癌细胞系的临床活性抗癌药物的相互作用。虽然依托泊苷、间-氨基吖啶、喜树碱和SN-38（CPT-11的活性代谢物）作为单一药物在杀死前列腺细胞方面具有活性，但苏拉明与这些药物的组合对这些细胞具有拮抗作用。我们发现，通过松弛和切割试验测定，苏拉明在体外抑制纯化的拓扑异构酶I和II的活性。进一步的研究表明，苏拉明在体外和分离的细胞核中也抑制药物诱导的DNA损伤。这些发现表明，苏拉明与拓扑异构酶抑制剂（例如VP-16、间-氨基吖啶或CPT）的组合可能对接受含苏拉明化疗的患者没有益处。
