Mutation Research 488 (2001) 25–37 Genotoxicity of streptonigrin: a review Alejandro D. Bolzán ∗ , Martha S. Bianchi Laboratory of Cytogenetics and Mutagenesis, Instituto Multidisciplinario de Biolog´ ıa Celular (IMBICE), C.C. 403, 1900 La Plata, Argentina Received 31 August 2000; accepted 21 November 2000 Abstract Streptonigrin (SN, CAS no. 3930-19-6) is an aminoquinone antitumor antibiotic isolated from cultures of Streptomyces flocculus. This compound is a member of a group of antitumor agents which possess the aminoquinone moiety and that includes also mitomycin C, porfiromycin, actinomycin, rifamycin and geldanamycin. Because of the potential use of SN in clinical chemotherapy, the study of its genotoxicity has considerable practical significance. SN inhibits the synthesis of DNA and RNA, causes DNA strand breaks after reduction with NADH, induces unscheduled DNA synthesis and DNA adducts and inhibits topoisomerase II. At the chromosome level, this antibiotic causes chromosome damage and increases the frequency of sister-chromatid exchanges. SN cleaves DNA in cell-free systems by a mechanism that involves complexing with metal ions and autoxidation of the quinone moiety to semiquinone in the presence of NADH with production of oxygen-derived reactive species. Recent evidence strongly suggests that the clastogenic action of this compound is partially mediated by free radicals. The present review aims at summarizing past and current knowledge concerning the genotoxic effects of SN. © 2001 Elsevier Science B.V. All rights reserved. Keywords: Streptonigrin; Genotoxicity; Bruneomycin 1. Introduction Streptonigrin (SN, CAS no. 3930-19-6) is an aminoquinone antitumor antibiotic isolated from cul- tures of Streptomyces flocculus [1]. Its molecular structure, shown in Fig. 1, was identified by chemical analysis and mass spectrometry by Rao et al. in 1963 [2] and confirmed by X-ray diffraction by Chiu and Lipscomb in 1975 [3]. It was shown that the A, B, and C rings are very nearly co-planar, and D ring is virtu- ally perpendicular to the other rings [3]. This finding was recently confirmed by Harding et al. [4] who ∗ Corresponding author. Tel.: +54-221-4210112; fax: +54-221-4253320. E-mail addresses: adbolzan@netverk.com.ar, imbice@netverk.com.ar (A.D. Bolz´ an). observed that the major conformation of SN in solu- tion coincides with the structure observed in the solid state. In 1968, Russian workers found that a substance called bruneomycin, isolated from Actinomyces albus var. bruneomycini, was identical to SN [5]. Recently, a mutant strain of Streptomyces helvaticus was also found to produce bruneomycin [6]. SN shows antitumor activity against a broad range of tumors, including breast, lung, head and neck can- cer, lymphoma and melanoma [2,7–12]. Its use in cancer therapy is limited because it induces severe and prolonged bone marrow depression [13–18]. How- ever, at least five studies report positive results with use of the antibiotic in the treatment of leukemias, lymphomas and melanomas [19–23]. Recently, it was found that SN can be efficiently bioactivated by DT-diaphorase, an enzyme showing increased 1383-5742/01/$ – see front matter © 2001 Elsevier Science B.V. All rights reserved. PII:S1383-5742(00)00062-4