Suramin inhibits DNA damage in human prostate cancer cells treated with topoisomerase inhibitors in vitro.
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.
Biochemical & Molecular Pharmacology Section, National Cancer Institute, NIH, Bethesda, MD 20892.
H
H
Yamazaki
A
A
Dilworth
C E
CE
Myers
B K
BK
Sinha
D000677:Amsacrine / Q000494:pharmacology / Q000633:toxicity; D002166:Camptothecin / Q000494:pharmacology / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D011232:Chemical Precipitation; D004249:DNA Damage / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005047:Etoposide / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000473:pathology*; D013498:Suramin / Q000494:pharmacology* / Q000633:toxicity; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D000677:Amsacrine; D013498:Suramin; D005047:Etoposide; D002166:Camptothecin