title: Brostallicin (PNU-166196), a new minor groove DNA binder: preclinical and clinical activity.
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.
authors: Catholic University of the Sacred Heart, Department of Gynecologic Oncology, Rome, Italy. kettalorusso@libero.it
authors: Domenica
authors: D
authors: Lorusso
authors: Sara
authors: S
authors: Mainenti
authors: Antonella
authors: A
authors: Pietragalla
authors: Gabriella
authors: G
authors: Ferrandina
authors: Gilda
authors: G
authors: Foco
authors: Valeria
authors: V
authors: Masciullo
authors: Giovanni
authors: G
authors: Scambia
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D002986:Clinical Trials as Topic; D004247:DNA / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D006146:Guanidines / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008956:Models, Chemical; D011758:Pyrroles / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D006146:Guanidines; D011758:Pyrroles; D004247:DNA; C455279:brostallicin