A novel 9-aza-anthrapyrazole effective against human prostatic carcinoma xenografts
| Autor: | Monica Tortoreto, Rosanna Supino, Raffaella Pavesi, Federica Facchinetti, Laura Dal Bo, Gabriella Pezzoni, Ernesto Menta, Silvia Richter, Dante Torriani, Claudia Sissi, Donatella Polizzi, Nives Carenini, Giovanni Capranico, Manlio Palumbo, Silvano Spinelli, Gino Beggiolin, Fulvio Guano, Franco Zunino, Graziella Pratesi |
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| Jazyk: | angličtina |
| Rok vydání: | 2001 |
| Předmět: |
Male
Cancer Research Pathology bcl-2 Nude genetics/metabolism Anthraquinones Apoptosis Mice Prostate Neoplasm Phosphorylation Pyrazolones Molecular Structure Remission Induction General Medicine DNA Neoplasm Intercalating Agents drug therapy Neoplasm Proteins DNA-Binding Proteins Gene Expression Regulation Neoplastic medicine.anatomical_structure Oncology Proto-Oncogene Proteins c-bcl-2 Ethanolamines Adenocarcinoma Oxidation-Reduction Cell Division human prostatic carcinoma medicine.medical_specialty Mice Nude Antineoplastic Agents Type II Anthrapyrazoles Aza-Anthrapyrazoles DNA interaction pharmacology/therapeutic use Animal model Antigens Neoplasm Carcinoma medicine Animals Humans Anthrapyrazole Antigens Protein Processing Neoplastic business.industry Post-Translational Prostatic Neoplasms DNA medicine.disease Xenograft Model Antitumor Assays Genes bcl-2 Oxidative Stress DNA Topoisomerases Type II Post translational Gene Expression Regulation Genes Doxorubicin therapeutic use drug effects Cancer research Pyrazoles biosynthesis business metabolism Protein Processing Post-Translational DNA Topoisomerases drug therapy Animals Anthraquinones therapeutic use Antigens Neoplasm Antineoplastic Agents pharmacology/therapeutic use Apoptosis drug effects Cell Division drug effects DNA Damage DNA Topoisomerases metabolism DNA drug effects DNA-Binding Proteins Doxorubicin therapeutic use Ethanolamines pharmacology/therapeutic use Gene Expression Regulation drug effects Genes bcl-2 Humans Intercalating Agents pharmacology/therapeutic use Male Mice Mice Nude Molecular Structure Neoplasm Proteins genetics/metabolism Oxidation-Reduction Oxidative Stress Phosphorylation Prostatic Neoplasms drug therapy Protein Processing drug effects Proto-Oncogene Proteins c-bcl-2 biosynthesis Pyrazoles pharmacology/therapeutic use Pyrazolones Remission Induction Xenograft Model Antitumor Assays DNA Damage |
| Popis: | Objectives: Systematic investigation of a novel series of intercalating agents, 9-aza-anthrapyrazoles, has led to the identification of a promising analogue, BBR 3438. This study describes the antitumour efficacy of the novel compound in human prostate carcinoma models and the molecular/cellular basis of its activity. Methods and Results: The novel 9-aza-anthrapyrazole BBR 3438 was significantly more effective than doxorubicin and losoxantrone (DuP-941) in two of the three tested prostate carcinoma models. The superior activity was more evident in PC3 tumour, since BBR 3438 produced an appreciable rate of complete tumour regressions. Under these conditions, the drug-induced antiproliferative activity paralleled delayed apoptosis. Tumour response to in vivo drug treatment was associated with an early down-regulation of Bcl-2, which was somewhat more marked for the aza compound. In fact, the 9-aza-anthrapyrazole induced DNA cleavage in vitro with isolated DNA topoisomerase II (isoform α) and DNA strand breaks in prostatic carcinoma cells. Although the molecular effects of losoxantrone and the 9-aza analogue on the enzyme target were comparable, the cytotoxic effects of BBR 3438 could be enhanced by long-term exposure as a consequence of favourable cellular accumulation and prominent DNA-binding affinity. In addition, a lower reduction potential of the 9-aza-anthrapyrazole in comparison with classical anthrapyrazoles suggests an increased ability of the drug to induce oxidative stress following free radical production, which may be a contributing factor in determining the long-term response (i.e. delayed cell death) to genotoxic damage. Conclusions: BBR 3438 exhibited a unique profile of preclinical activity with a superior efficacy against prostatic carcinoma models compared to reference compounds (doxorubicin and losoxantrone). The antitumour efficacy of BBR 3438 against prostatic carcinoma could be the result of a combination of favourable events, including enhanced intracellular accumulation and an increased DNA-binding affinity favouring the accumulation of multiple sublethal or lethal damage. In spite of its enhanced cytotoxic potency, the 9-aza compound was better tolerated in vivo than losoxantrone, thus improving the therapeutic index. The preclinical profile of efficacy against prostatic carcinoma, a tumour resistant to conventional antitumour drugs, makes the novel 9-aza-anthrapyrazole BBR 3438 a promising candidate for clinical evaluation. |
| Databáze: | OpenAIRE |
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