Topic
Brostallicin
About: Brostallicin is a research topic. Over the lifetime, 29 publications have been published within this topic receiving 485 citations. The topic is also known as: Brostallicin.
Papers
Journal Article•
TL;DR: The antitumor activity of brostallicin was higher in the GST-pi-overexpressing tumors without increased toxicity, and it was speculated that an intracellular reactive nucleophilic species, e.g., GSH, could react with the alpha-bromoacrylamide moiety functions.
Abstract: Brostallicin (PNU-166196) is a synthetic alpha-bromoacrylic, second-generation DNA minor groove binder structurally related to distamycin A, presently in Phase II trials in Europe and the United States. The compound shows broad antitumor activity in preclinical models and dramatically reduced in vitro myelotoxicity in human hematopoietic progenitor cells compared with that of other minor groove binders. Brostallicin showed a 3-fold higher activity in melphalan-resistant L1210 murine leukemia cells than in the parental line (IC(50) = 0.46 and 1.45 ng/ml, respectively) under conditions in which the cytotoxicity of conventional antitumor agents was either unaffected or reduced. This melphalan-resistant cell line has increased levels of glutathione (GSH) in comparison with the parental cells. Conversely, GSH depletion by buthionine sulfoximine in a human ovarian carcinoma cell line (A2780) significantly decreased both the cytotoxic and the proapoptotic effects of brostallicin. In one experiment, human glutathione S-transferase pi (GST-pi) cDNA was transfected into A2780 cells, and four clones of A2780 with different expression levels of GST-pi were generated (i.e., two clones with high and two clones with low GST-pi expression). A 2-3-fold increase in GST-pi levels resulted in a 2-3-fold increase in cytotoxic activity of brostallicin. Similar results were obtained for GST-pi-transfected human breast carcinoma cells (MCF-7). Brostallicin showed 5.8-fold increased cytotoxicity in GST-pi-transfected versus empty vector-transfected cells with low GST-pi expression. In an in vivo experiment, A2780 clones were implanted into nude mice. The antitumor activity of brostallicin was higher in the GST-pi-overexpressing tumors without increased toxicity. Regarding the mechanism of action, brostallicin interacts reversibly with the DNA minor groove TA-rich sequences but appears unreactive in classical in vitro DNA alkylation assays. We speculated that an intracellular reactive nucleophilic species, e.g., GSH, could react with the alpha-bromoacrylamide moiety functions. Experiments on the interaction with plasmid DNA showed a change of the DNA topology from supercoiled to circular form (nicking) in the presence of GSH, whereas no change was found in its absence. In vitro incubations of brostallicin were performed with the human recombinant GST isoenzymes A1-1, M1-1, and P1-1 (alpha, mu and pi isoenzymes, respectively) in the presence of GSH. The decrease in brostallicin levels was monitored in these incubations; the rate of loss (and therefore brostallicin metabolism) was significantly higher for the M1-1 and P1-1 isoenzymes than for the A1-1 isoenzyme.
64 citations
TL;DR: In particular brostallicin (PNU-166196), alpha-bromo-acrylamido tetra-pyrrole derivative ending with a guanidino moiety, showed high cytotoxic potency and myelotoxicity dramatically reduced in comparison to TAM and other MGB.
Abstract: DNA minor groove binders (MGB) represent a class of anticancer agents whose DNA sequence specificity was hypothesized to lead to high selectivity of action. Tallimustine (TAM), a benzoyl nitrogen mustard derivative of distamycin A (DST), showed excellent antitumor activity in preclinical tests, but also a severe myelotoxicity. Novel nitrogen mustard, nitrogen half-mustard and sulfur mustard derivatives of DST showing excellent activity were recently identified and SAR reported. In particular nitrogen half-mustard and sulfur mustard derivatives, as one-arm alkylating agents, represent interesting structural novelties. A further new class of cytotoxic anticancer agents is that of α-halogenoacrylamido derivatives of DST-like oligopeptides, which show an activity profile substantially improved in comparison to TAM. In particular brostallicin (PNU-166196), α-bromo-acrylamido tetra-pyrrole derivative ending with a guanidino moiety, showed high cytotoxic potency and myelotoxicity dramatically reduced in comparison to TAM and other MGB. Brostallicin binds to the minor groove but appears unreactive in classical in vitro DNA alkylation assays. About the apparent lack of DNA alkylation we speculated that an intracellular nucleophile, e.g. glutathione (GSH), could activate the reactivity of the compound leading to alkylation of DNA in vivo. Evidence of both covalent interaction of brostallicin with plasmidic DNA in the presence of GSH and of enhanced cytotoxicity in cancer cells characterized by high levels of GSH were obtained. Brostallicin was selected for clinical development and is now undergoing Phase II studies.
52 citations
TL;DR: The study assessed the efficacy and safety of brostallicin, a new DNA minor groove binder, at a dose of 10mg/m2, intravenous every three weeks, in patients with advanced or inoperable soft tissue sarcoma (STS) and gastrointestinal stromal tumour (GIST) failing first line therapy.
48 citations
TL;DR: Broidstallicin (PNU-166196) as mentioned in this paper is an α-bromo-acrylamido tetra-pyrrole derivative with a guanidino moiety.
Abstract: DNA minor groove binders (MGB) represent a class of anticancer agents whose DNA sequence specificity was hypothesized to lead to high selectivity of action. Tallimustine (TAM), a benzoyl nitrogen mustard derivative of distamycin A (DST), showed excellent antitumor activity in preclinical tests, but also a severe myelotoxicity. Novel nitrogen mustard, nitrogen half-mustard and sulfur mustard derivatives of DST showing excellent activity were recently identified and SAR reported. In particular nitrogen half-mustard and sulfur mustard derivatives, as one-arm alkylating agents, represent interesting structural novelties. A further new class of cytotoxic anticancer agents is that of α-halogenoacrylamido derivatives of DST-like oligopeptides, which show an activity profile substantially improved in comparison to TAM. In particular brostallicin (PNU-166196), α-bromo-acrylamido tetra-pyrrole derivative ending with a guanidino moiety, showed high cytotoxic potency and myelotoxicity dramatically reduced in comparison to TAM and other MGB. Brostallicin binds to the minor groove but appears unreactive in classical in vitro DNA alkylation assays. About the apparent lack of DNA alkylation we speculated that an intracellular nucleophile, e.g. glutathione (GSH), could activate the reactivity of the compound leading to alkylation of DNA in vivo. Evidence of both covalent interaction of brostallicin with plasmidic DNA in the presence of GSH and of enhanced cytotoxicity in cancer cells characterized by high levels of GSH were obtained. Brostallicin was selected for clinical development and is now undergoing Phase II studies.
38 citations
TL;DR: 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, and a clear therapeutic advantage is observed when broStallicin is combined with anticancer agents such as cisplatin, doxorubicin, irinotecan and docetaxel.
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.
30 citations
Related Topics (5)
Performance Metrics
| Year | Papers |
|---|---|
| 2014 | 1 |
| 2013 | 1 |
| 2010 | 3 |
| 2009 | 4 |
| 2008 | 1 |
| 2007 | 3 |