Brostallicin (PNU-166196), a new minor groove DNA binder: Preclinical and clinical activity

Domenica Lorusso, Sara Mainenti, Antonella Pietragalla, Gabriella Ferrandina, Gilda Foco, Valeria Masciullo, Giovanni Scambia

Research output: Contribution to journalArticle

Abstract

Brostallicin (PNU-166196), a-bromo-acrylamido tetra-pyrrole derivative, showed high cytotoxic potency and myelotoxicity dramatically reduced compared with other minor groove DNA-binding agents. In the presence of high intracellular glutathione concentrations, which are associated with resistance to chemotherapy, brostallicin performs a DNA minor groove attack leading to alkylation of DNA nucleophilic functions. In preclinical models, the antitumor activity of brostallicin has been tested in ovarian cancer xenografts, L1210 murine leukemia models, renal, colon and prostatic cancer cells and glutathione-S-transferase (GST) transfected human breast carcinoma cells. In clinical setting, the antitumor activity of brostallicin has been tested in ovarian cancer and in soft tissue sarcoma patients. A clear therapeutic advantage is also observed in preclinical models when brostallicin is combined with anticancer agents such as cisplatin (CDDP), doxorubicin, irinotecan and docetaxel. Brostallicin was also tested in combination with gefitinib, imatinib and bevacizumab in in vitro and in vivo studies, documenting a synergistic effect and with cetuximab showing an additive effect. Preliminary results of activity and toxicities of brostallicin in Phase I and II studies will be provided.

Original languageEnglish
Pages (from-to)1939-1946
Number of pages8
JournalExpert Opinion on Investigational Drugs
Volume18
Issue number12
DOIs
Publication statusPublished - Dec 2009

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Keywords

  • Brostallicin
  • Chemotherapy
  • DNA minor groove-binding agent
  • PNU-166196

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Lorusso, D., Mainenti, S., Pietragalla, A., Ferrandina, G., Foco, G., Masciullo, V., & Scambia, G. (2009). Brostallicin (PNU-166196), a new minor groove DNA binder: Preclinical and clinical activity. Expert Opinion on Investigational Drugs, 18(12), 1939-1946. https://doi.org/10.1517/13543780903401284