title: A novel 9-aza-anthrapyrazole effective against human prostatic carcinoma xenografts.
abstract: OBJECTIVE
  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.
  
  
  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 alpha) 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.
authors.affiliation: Istituto Nazionale Tumori, Milano, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Supino
authors.forename: D
authors.initials: D
authors.lastname: Polizzi
authors.forename: R
authors.initials: R
authors.lastname: Pavesi
authors.forename: G
authors.initials: G
authors.lastname: Pratesi
authors.forename: F
authors.initials: F
authors.lastname: Guano
authors.forename: G
authors.initials: G
authors.lastname: Capranico
authors.forename: M
authors.initials: M
authors.lastname: Palumbo
authors.forename: C
authors.initials: C
authors.lastname: Sissi
authors.forename: S
authors.initials: S
authors.lastname: Richter
authors.forename: G
authors.initials: G
authors.lastname: Beggiolin
authors.forename: E
authors.initials: E
authors.lastname: Menta
authors.forename: G
authors.initials: G
authors.lastname: Pezzoni
authors.forename: S
authors.initials: S
authors.lastname: Spinelli
authors.forename: D
authors.initials: D
authors.lastname: Torriani
authors.forename: N
authors.initials: N
authors.lastname: Carenini
authors.forename: L
authors.initials: L
authors.lastname: Dal Bo
authors.forename: F
authors.initials: F
authors.lastname: Facchinetti
authors.forename: M
authors.initials: M
authors.lastname: Tortoreto
authors.forename: F
authors.initials: F
authors.lastname: Zunino
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000818:Animals; D000880:Anthraquinones / Q000627:therapeutic use; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004273:DNA, Neoplasm / Q000187:drug effects; D004268:DNA-Binding Proteins; D004317:Doxorubicin / Q000627:therapeutic use; D004983:Ethanolamines / Q000494:pharmacology / Q000627:therapeutic use*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019254:Genes, bcl-2; D006801:Humans; D007364:Intercalating Agents / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D047069:Pyrazolones; D012074:Remission Induction; D023041:Xenograft Model Antitumor Assays
chemical_list: D000880:Anthraquinones; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; C439071:BBR 3438; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D004983:Ethanolamines; D007364:Intercalating Agents; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011720:Pyrazoles; D047069:Pyrazolones; C050637:losoxantrone; D004317:Doxorubicin; D004250:DNA Topoisomerases, Type II