Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity

Minotti, Giorgio; Menna, Pierantonio; Salvatorelli, Emanuela; Cairo, Gaetano; Gianni, Luca

doi:10.1124/pr.56.2.6

Cited by 3,174 publications

(2,973 citation statements)

References 314 publications

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“…Direct membrane effects have also been associated with DXR treatment. 11 All these actions profoundly affect DNA function in exposed cells; by provoking erroneous transcription and/or replication, and eventually causing demise of the cell.…”

Section: Introductionmentioning

confidence: 99%

Molecular requirements for doxorubicin-mediated death in murine oocytes

Jurisicova

et al. 2006

Cell Death Differ

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We previously published evidence that oocytes exposed to doxorubicin (DXR), a widely used chemotherapeutic agent, rapidly undergo morphological and biochemical changes via discrete effector signaling pathways consistent with the occurrence of apoptosis. In this report, we elucidated the molecular requirements for actions of this drug in oocytes. Our results indicate that within 1 h of exposure DXR causes rapid DNA damage, and commits the oocyte to cytoplasmic fragmentation by the fourth hour, followed by delayed oocyte activation and execution of cytoplasmic fragmentation. Inhibitors that interfere with oocyte activation consistently rescue cytoplasmic fragmentation, but fail to suppress DNA damage. There was evidence of depletion of Bax, Caspase-2, MA-3 and Bcl-x transcripts, suggesting that modulations by DXR caused recruitment of these maternal transcripts into the translation process. Furthermore, sphingolipids such as sphingosine-1-phosphate and ceramide modulate DXR actions by, respectively, altering its intracellular trafficking, or by sustaining the drug's contact with DNA.

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Section: Introductionmentioning

confidence: 99%

Molecular requirements for doxorubicin-mediated death in murine oocytes

Jurisicova

et al. 2006

Cell Death Differ

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“…Anthracyclines are highly effective chemotherapeutic agents used in treating a broad range of malignancies (Minotti et al, 2004). Their discovery in the 1960s and subsequent introduction into clinical practice led to significant improvements in the treatment of some cancers, most particularly lymphomas, breast cancer and sarcoma.…”

Section: Anthracycline Therapymentioning

confidence: 99%

“…More recently, they are increasingly used in the treatment of non-metastatic gastric and lower oesophageal cancers, breast, ovarian and lung cancers (Cortes-Funes and Coronado, 2007). Although effective, these drugs have serious side effects, most notably cardiotoxicity, which is often under-reported because of it's late onset, and is becoming more of a clinical issue as treatments result in more long-term survivors of cancer, and as these drugs are increasingly offered to older patients (Eifel et al, 2001;Minotti et al, 2004). Two of the most commonly used anthracyclines are epirubicin and doxorubicin.…”

Section: Anthracycline Therapymentioning

confidence: 99%

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Targeting anthracyclines in early breast cancer: new candidate predictive biomarkers emerge

2010

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The search for a predictive marker of sensitivity to anthracycline-based chemotherapy has proven challenging. Despite human epidermal growth factor receptor 2 (HER2) being a strong prognostic marker in breast cancer, the only therapies with which there is a recognized functional link to the HER2 oncogene are those directly targeting the molecule itself. Despite this, HER2 has been extensively assessed as a predictive marker in a variety of chemotherapy regimens including anthracyclines. Analysis of anthracycline response in patients with HER2 amplification has given conflicting results. This led to the suggestion that HER2 amplification was acting as a surrogate for the gene encoding topoisomerase IIa (TOP2A), a direct cellular target of anthracyclines. Despite an attractive functional link between TOP2A and anthracyclines, published studies have failed to show strong evidence of an interaction between TOP2A genetic aberrations and anthracycline response. A number of other biomarkers have also been assessed for their role in predicting anthracycline response, including TP53 (tumour protein 53) and BRCA1 (breast cancer 1, early onset), together with an increasing emergence of gene expression profiling to produce predictive signatures of response. Moreover, recent evidence has emerged from presentations suggesting new candidate markers of response that warrant further investigation: Chr17CEP duplication and tissue inhibitor of metalloproteases 1. This review will discuss research into HER2 and TOP2A as predictive markers of anthracycline response and will focus on current research into other possible candidate predictive markers.

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“…Anthracyclines are chemotherapeutic agents from Streptomyces bacteria that are used extensively as anticancer therapeutics in the clinic 9. Among the cancers that are being treated with anthracyclines are bladder, breast, lung and ovarian cancers, leukemias and lymphomas 10. Their mode of action continues to be studied, both experimentally and with computational methods 11.…”

Section: Introductionmentioning

confidence: 99%

Encapsulating Active Pharmaceutical Ingredients in Self‐Assembling Adamantanes with Short DNA Zippers

2017

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Formulating pharmaceutically active ingredients for drug delivery is a challenge. There is a need for new drug delivery systems that take up therapeutic molecules and release them into biological systems. We propose a novel mode of encapsulation that involves matrices formed through co‐assembly of drugs with adamantane hybrids that feature four CG dimers as sticky ends. Such adamantanes are accessible via inexpensive solution‐phase syntheses, and the resulting materials show attractive properties for controlled release. This is demonstrated for two different hybrids and a series of drugs, including anticancer drugs, antibiotics, and cyclosporin. Up to 20 molar equivalents of active pharmaceutical ingredients (APIs) are encapsulated in hybrid materials. Encapsulation is demonstrated for DNA‐binding and several non‐DNA binding compounds. Nanoparticles were detected that range in size from 114–835 nm average diameter, and ζ potentials were found to be between −29 and +28 mV. Release of doxorubicin into serum at near‐constant rates for 10 days was shown, demonstrating the potential for slow release. The encapsulation and release in self‐assembling matrices of dinucleotide‐bearing adamantanes appears to be broadly applicable and may thus lead to new drug delivery systems for APIs.

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Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity

Cited by 3,174 publications

References 314 publications

Molecular requirements for doxorubicin-mediated death in murine oocytes

Molecular requirements for doxorubicin-mediated death in murine oocytes

Targeting anthracyclines in early breast cancer: new candidate predictive biomarkers emerge

Encapsulating Active Pharmaceutical Ingredients in Self‐Assembling Adamantanes with Short DNA Zippers

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