‘Daunomycin’, a New Antibiotic of the Rhodomycin Group

A, Dimarco; Gaetani, Maurizio; Orezzi, P.; Scarpinato, B.; Silvestrini, Rosella; Soldati, M; Dasdia, T; Valentini, Laura

doi:10.1038/201706a0

Cited by 256 publications

(131 citation statements)

References 16 publications

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“…24) The glycosidic bond between the daunosamine ring and the aglycone moiety is hydrolysed relatively easily, releasing the free aglycone. 33) The hydrolysis method detected the aglycone of DOX which can be estimated as the PVA-bound DOX selectively. The DOX content estimated by this method was 4.4 w/w% which was similar to 4.6 w/w% by the UV method.…”

Section: Discussionmentioning

confidence: 99%

Synthesis of Poly(vinyl alcohol)-Doxorubicin Conjugates Containing cis-Aconityl Acid-Cleavable Bond and Its Isomer Dependent Doxorubicin Release

Kakinoki

Kaneo

Ikeda

et al. 2008

Biological & Pharmaceutical Bulletin

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Aconityl-doxorubicin (ADOX) was synthesized by the modified method of Shen and Ryser. Two isomers of cis-ADOX (cis-configuration) and trans-ADOX (trans-configuration) were generated in the reaction of DOX and cis-aconitic anhydride. These products were separated completely by using HPLC and analyzed by TOF-MS spectroscopy and 1 H-and 13 C-NMR experiments. The yields of cis-ADOX and trans-ADOX were 36.3 and 44.8%, respectively. The free g g-carboxylic group of ADOX molecule was coupled to poly(vinyl alcohol) (PVA) via ethylenediamine spacer, resulting the macromolecular conjugates of PVA-cis-ADOX and PVA-trans-ADOX, respectively. The DOX content of the conjugates estimated by the hydrolysis method detected the aglycone of DOX which can be estimated as the PVA-bound DOX selectively was 4.4 w/w% which was similar to 4.6 w/w% by the ordinary UV method. Both PVA-cis-ADOX and PVA-trans-ADOX were very stable at neutral pH, but the release of DOX was increased markedly under acidic conditions. Half-life of the release of DOX from PVA-cis-ADOX at pH 5.0 was 3 h which was 4.7-fold shorter than that from PVA-trans-ADOX (14 h). The cytotoxicities of PVA-cis-ADOX and PVA-trans-ADOX were evaluated by using J774.1 cells employing a [ 3 H]uridine incorporation assay as a measure of RNA synthesis. A significant difference in antitumor activity between PVA-cis-ADOX and PVA-trans-ADOX was observed where the former was much active than the later. It was suggested that the conjugate enters the cells and reaches the lysosomal/endosomal compartment, and that the aconityl spacer releases DOX from the conjugate in the acidic compartment of lysosomes/endosomes due to the participation of a free carboxylic group.

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Section: Discussionmentioning

confidence: 99%

Synthesis of Poly(vinyl alcohol)-Doxorubicin Conjugates Containing cis-Aconityl Acid-Cleavable Bond and Its Isomer Dependent Doxorubicin Release

Kakinoki

Kaneo

Ikeda

et al. 2008

Biological & Pharmaceutical Bulletin

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“…Taking advantage of daunomycin's intrinsic fluorescence, it was possible to relate cytotoxicity to strong chromosomal aberrations and nuclear damage as well as to decrease in nucleolar size (23). An important report presented by Prof. Di Marco at the III International Congress of Chemotherapy (July [22][23][24][25][26][27]1963) in Stuttgart, Germany (24), was followed by a seminal paper on February 15, 1964 (25), both showing the efficacy of daunomycin in experimental tumor models. In particular, the second report presented further data on the mechanism of action, evidencing that daunomycin could strongly bind to DNA, interfering with its functions also as a primer in RNA synthesis and in mitosis (25).…”

Section: The Multiform and Eclectic Streptomyces Fi 1762mentioning

confidence: 99%

The Roots of Modern Oncology: From Discovery of New Antitumor Anthracyclines to their Clinical Use

Cassinelli

2016

Tumori

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In May 1960, the Farmitalia CEO Dr. Bertini and the director of the Istituto Nazionale dei Tumori of Milan Prof. Bucalossi (talent scout and city's Mayor) signed a research agreement for the discovery and development up to clinical trials of new natural antitumor agents. This agreement can be considered as a pioneering and fruitful example of a translational discovery program with relevant transatlantic connections. Owing to an eclectic Streptomyces, found near Castel del Monte (Apulia), and to the skilled and motivated participants of both institutions, a new natural antitumor drug, daunomycin, was ready for clinical trials within 3 years. Patent interference by the Farmitalia French partner was overcome by the good quality of the Italian drug and by the cooperation between Prof. Di Marco, director of the Istituto Ricerche Farmitalia Research Laboratories for Microbiology and Chemotherapy, and Prof. Karnofsky, head of the Sloan-Kettering Cancer Institute of New York, leading to the first transatlantic clinical trials. The search for daunomycin's sister anthracyclines led to the discovery and development of adriamycin, one of the best drugs born in Milan. This was the second act prologue of the history of Italian antitumor discovery and clinical oncology, which started in July 1969 when Prof. Di Marco sent Prof. Bonadonna the first vials of adriamycin (doxorubicin) to be tested in clinical trials. This article reviews the Milan scene in the 1960s, a city admired and noted for the outstanding scientific achievements of its private and public institutions in drugs and industrial product discovery.

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“…They were recognized as early as 1939 for their antibacterial properties (1) and have been used as important anti-tumor drugs in chemotherapy for more than three decades (2). Their mode of action is not yet fully understood, but there is evidence that their cytotoxic activity is at least in part because of inhibition of topoisomerase II (3).…”

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confidence: 99%