Antitumor anthracyclines: Recent developments

Arcamone, Federico

doi:10.1002/med.2610040203

Cited by 96 publications

(27 citation statements)

References 101 publications

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“…Three such anthracyclines, adriamycin (also known as doxorubicin), daunomycin (also known as daunorubicin) and aclacinomycin A, are used extensively as chemotherapeutic agents but are cumulatively cardiotoxic and have destructive side-effects when used for long periods of time (Arcamone, 1984). Therefore, new anthracyclines with enhanced clinical properties have been sought intensively (reviewed by Fujiwara & Hoshino, 1983;Strohl et al, 1989).…”

Section: Introductionmentioning

confidence: 99%

Biosynthesis of anthracyclines: analysis of mutants of Streptomyces sp. strain C5 blocked in daunomycin biosynthesis

Batel

Connors

Strohl

1990

Journal of General Microbiology

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~~~~~ ~~Streptomyces sp. strain C5, an organism that normally produces baumycins, daunomycin and E-rhodomycinone, was treated with N-methyl-N'-nitro-N-nitrosoganidine (NTG). Mutants blocked at various points in daunomycin and baumycin production were isolated by screening for altered pigmentation and absence of bioactivity against Staphyfococcus aureus. Examination of the mutants by thin-layer chromatography of their accumulated anthracycline metabolites, by cosynthesis assays, and by extract feeding experiments allowed a classification into six groups. These were: dauA, strains that accumulated no anthracyclines but with other blocked mutants cosynthesized anthracyclines (polyketide-synthase-minus mutants); dauG, regulatory mutants that, either alone or mixed with other blocked mutants, accumulated no anthracyclines; d a d , mutants that accumulated aklanonic acid; dauE, mutants that accumulated maggiemycin; dauF, mutants that accumulated aklavinone; and dauH, mutants that accumulated only E-rhodomycinone. Mutant SC5-24 (dauE), which accumulated the shunt product maggiemycin, was re-mutagenized with NTG to obtain blocked mutants in preceding biosynthetic steps; the three groups of double mutants obtained accumulated aklanonic acid (dauC,E), aklanonic acid methyl ester (dauD,E) and aklaviketone (dauE,F).

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Section: Introductionmentioning

confidence: 99%

Biosynthesis of anthracyclines: analysis of mutants of Streptomyces sp. strain C5 blocked in daunomycin biosynthesis

Batel

Connors

Strohl

1990

Journal of General Microbiology

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“…caesius, a gram-positive soil bacterium with high GϩC content (1,11,18). Like the biosynthesis of other secondary metabolites in Streptomyces species, the synthesis of doxorubicin is believed to be tightly regulated, thereby limiting doxorubicin production in wild-type-S. peucetius cultures (6,12,17).…”

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Interspecies DNA Microarray Analysis Identifies WblA as a Pleiotropic Down-Regulator of Antibiotic Biosynthesis in Streptomyces

et al. 2007

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Using Streptomyces coelicolor microarrays to discover regulators of gene expression in other Streptomyces species, we identified wblA, a whiB-like gene encoding a putative transcription factor, as a down-regulator of doxorubicin biosynthesis in Streptomyces peucetius. Further analysis revealed that wblA functions pleiotropically to control antibiotic production and morphological differentiation in streptomycetes. Our results reveal a novel biological role for wblA and show the utility of interspecies microarray analysis for the investigation of streptomycete gene expression.

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“…1) are clinically important anthracycline chemotherapeutic agents. Daunomycin is used primarily to treat adult myelogenous leukemia, whereas doxorubicin is widely used to treat a variety of neoplasias (2), making it the more valuable of these antitumor drugs (36). Daunomycin was discovered in the early 1960s (9,15) by research groups at Rhône-Poulenc and Farmitalia.…”

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confidence: 99%

Isolation and characterization of a gene from Streptomyces sp. strain C5 that confers the ability to convert daunomycin to doxorubicin on Streptomyces lividans TK24

Dickens

Strohl

1996

J Bacteriol

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DNA sequence analysis of a region of the Streptomyces sp. strain C5 daunomycin biosynthesis gene cluster, located between the daunomycin polyketide biosynthesis gene cluster and a dnrI (transcriptional activator) homolog, revealed the presence of a gene encoding a P-450-like enzyme with a deduced M r of 46,096. Expression of this gene, named herein doxA, in Streptomyces lividans TK24 resulted in in vivo bioconversion of daunomycin to doxorubicin. DoxA showed specificity for only daunomycin and 13-dihydrodaunomycin, both of which were converted to doxorubicin. Daunomycinone (daunomycin aglycone), carminomycin, 13-dihydrocarminomycin, idarubicin, and aklavin were not apparent substrates for DoxA. In vector controls or in vectors in which doxA was poorly expressed, S. lividans catalyzed the reduction of daunomycin and other 13-oxo-anthracyclines and -anthracyclinones to their 13-dihydro homologs.

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Antitumor anthracyclines: Recent developments

Cited by 96 publications

References 101 publications

Biosynthesis of anthracyclines: analysis of mutants of Streptomyces sp. strain C5 blocked in daunomycin biosynthesis

Biosynthesis of anthracyclines: analysis of mutants of Streptomyces sp. strain C5 blocked in daunomycin biosynthesis

Interspecies DNA Microarray Analysis Identifies WblA as a Pleiotropic Down-Regulator of Antibiotic Biosynthesis in Streptomyces

Isolation and characterization of a gene from Streptomyces sp. strain C5 that confers the ability to convert daunomycin to doxorubicin on Streptomyces lividans TK24

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