25 results match your criteria brostallicin

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Brostallicin versus doxorubicin as first-line chemotherapy in patients with advanced or metastatic soft tissue sarcoma: an European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group randomised phase II and pharmacogenetic study.

Eur J Cancer 2014 Jan 8;50(2):388-96. Epub 2013 Nov 8.

Department of Surgery, Klinikum Mannheim, University of Heidelberg, Germany.

Aim: Brostallicin is a DNA minor groove binder that has shown activity in patients with soft tissue sarcoma (STS) failing first-line therapy. The present study assessed the safety and efficacy of first-line brostallicin in patients with advanced or metastatic STS >60 years or not fit enough to receive combination chemotherapy. A prospective explorative pharmacogenetic analysis was undertaken in parallel. Read More

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January 2014

Zebularine partially reverses GST methylation in prostate cancer cells and restores sensitivity to the DNA minor groove binder brostallicin.

Epigenetics 2013 Jun 14;8(6):656-65. Epub 2013 Jun 14.

Laboratory of Molecular Pharmacology; Department of Oncology; IRCCS-Istituto di Ricerche Farmacologiche Mario Negri; Milan, Italy.

Brostallicin is a DNA minor groove binder that shows enhanced antitumor activity in cells with high glutathione S-transferase (GST)/glutathione content. Prostate cancer cells present, almost invariably, methylation of the GSTP1 gene promoter and, as a consequence, low levels of GST-pi expression and activity. In these cells, brostallicin shows very little activity. Read More

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Thiol-activated DNA damage by α-bromo-2-cyclopentenone.

Chem Res Toxicol 2011 Feb 20;24(2):217-28. Epub 2011 Jan 20.

Department of Chemistry, University of Missouri, 125 Chemistry Building Columbia, Missouri 65211, United States.

Some biologically active chemicals are relatively stable in the extracellular environment but, upon entering the cell, undergo biotransformation into reactive intermediates that covalently modify DNA. The diverse chemical reactions involved in the bioactivation of DNA-damaging agents are both fundamentally interesting and of practical importance in medicinal chemistry and toxicology. The work described here examines the bioactivation of α-haloacrolyl-containing molecules. Read More

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February 2011

Testing new regimens in patients with advanced soft tissue sarcoma: analysis of publications from the last 10 years.

Ann Oncol 2011 Jun 23;22(6):1266-1272. Epub 2010 Dec 23.

European Organisation for Research and Treatment of Cancer Headquarters, EORTC, Brussels, Belgium; European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group, EORTC, Brussels, Belgium; Division of Surgical Oncology and Thoracic Surgery, Department of Surgery, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

Background: The prognosis of advanced soft tissue sarcoma remains poor. Many phase II trials investigating new regimens have been published in the last 10 years.

Materials And Methods: Full English-language reports of phase II clinical trials from January 1999 to October 2009 have been reviewed. Read More

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Phase I dose-escalation study of brostallicin, a minor groove binder, in combination with cisplatin in patients with advanced solid tumors.

Cancer Chemother Pharmacol 2010 Jul 22;66(2):389-94. Epub 2009 Nov 22.

National Tumor Institute, Naples, Italy.

Purpose: Brostallicin is a DNA minor groove binder which shows enhanced antitumor activity in cells which are resistant to several anticancer agents due to their high glutathione S-transferase (GST)/glutathione content. Phase I and II clinical trials of single-agent brostallicin have shown that myelotoxicity is the dose-limiting toxicity (DLT), while hints of antitumor activity were mainly observed in soft tissue sarcoma. Preclinical studies showing a more than additive antitumor effect of the cisplatin-brostallicin combination paved the way to clinical combination studies. Read More

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Role of glutathione transferases in the mechanism of brostallicin activation.

Biochemistry 2010 Jan;49(1):226-35

Department of Chemical Sciences and Technologies, University of Tor Vergata, Rome, Italy.

Brostallicin is a novel and unique glutathione transferase-activated pro-drug with promising anticancer activity, currently in phase I and II clinical evaluation. In this work, we show that, in comparison with the parental cell line showing low GST levels, the cytotoxic activity of brostallicin is significantly enhanced in the human breast carcinoma MCF-7 cell line, transfected with either human GST-pi or GST-mu. Moreover, we describe in detail the interaction of brostallicin with GSH in the presence of GSTP1-1 and GSTM2-2, the predominant GST isoenzymes found within tumor cells. Read More

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January 2010

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

Expert Opin Investig Drugs 2009 Dec;18(12):1939-46

Catholic University of the Sacred Heart, Department of Gynecologic Oncology, Rome, Italy.

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. Read More

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December 2009

Induction of glutathione-dependent DNA double-strand breaks by the novel anticancer drug brostallicin.

Mol Cancer Ther 2009 Jul 7;8(7):1985-94. Epub 2009 Jul 7.

Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892-4255, USA.

Brostallicin is a DNA minor groove binder in phase II clinical trials. Here, we show that brostallicin induces gamma-H2AX nuclear foci that colocalize with 53BP1 and are dependent on glutathione, as shown by inhibition of those gamma-H2AX foci by l-buthionine sulfoximine. To differentiate brostallicin from the clinically approved minor groove binder trabectedin (ecteinascidin 743), we tested whether the brostallicin-induced gamma-H2AX and antiproliferative responses were dependent on nucleotide excision repair and found that, unlike trabectedin, they are not. Read More

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alpha-halogenoacrylic derivatives of antitumor agents.

Mini Rev Med Chem 2009 Jan;9(1):81-94

Dipartimento di Scienze Farmaceutiche, Università di Ferrara, Via Fossato di Mortara 17-19, 44100-Ferrara, Italy.

In this review article we have reported a series of hybrid compounds characterized by the presence of a alpha-halogenocryloyl alkylating moiety of low chemical reactivity, linked to known antitumor agents or their active moieties. Among them, brostallicin (PNU-166196), was selected for clinical development and is now undergoing Phase II studies in patients with advanced or metastatic soft tissue sarcoma. Read More

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January 2009

Gateways to clinical trials.

Methods Find Exp Clin Pharmacol 2007 Jun;29(5):359-73

Prous Science, S.A., PO Box 540,08080 Barcelona, Spain.

101M, 12B75; ABT-869, Agomelatine, Alvocidib hydrochloride, Amb a 1 ISS-1018, AMG-386, Andolast, AP-23573, Arsenic trioxide, ATI-7505; BAY-68-4986, Berberine chloride, BNP-1350, BrachySil, Brostallicin hydrochloride; Caldaret hydrate, Cancer vaccine, Cediranib, CHAMPION everolimus-eluting coronary stent, CP-751871; D-4F, Degarelix acetate, Dofequidar fumarate; Ecogramostim, Enzastaurin hydrochloride, Etaracizumab, Everolimus; Fluticasone furoate; Glucarpidase; Hochuekki-to, Human papillomavirus vaccine; Icatibant acetate, INO-1001, Interleukin-21, Irofulven, ISIS-301012, Ixabepilone; KRN-951; Lacosamide; Mecasermin, Mecasermin rinfabate, Mepolizumab, Mesna disulfide, m-NO-ASA; Nematode anticoagulant protein c2, Nilotinib, Nolatrexed dihydrochloride; O6-Benzylguanine; Pemetrexed disodium, Perifosine, Pertuzumab, Plitidepsin, Prasterone, PRO-2000/5, PX-12, Pyridoxal phosphate; Recombinant human soluble thrombomodulin, Retapamulin, Rinfabate, Rubitecan; Seliciclib, SR-271425, STA-4783; T- 2000, Telatinib, Temsirolimus, Terameprocol, Teverelix, Ticagrelor, Tipelukast, Tirapazamine; Uracil; Valspodar, Vatalanib succinate, Velimogene aliplasmid, Vitespen, Volociximab; XL-184. Read More

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Systemic treatment options for patients with refractory adult-type sarcoma beyond anthracyclines.

Authors:
Jörg T Hartmann

Anticancer Drugs 2007 Mar;18(3):245-54

Medical Center II, South West German Cancer Center, Eberhard-Karls-University, Tuebingen, Germany.

For the subgroup of patients with inoperable gastrointestinal stromal tumors, progress has been made by the rapid development and approval of the targeted therapy imatinib mesylate. Small round cell sarcoma, such as Ewing/PNET, desmoplastic small round cell sarcoma and rhabdomyosarcoma, are chemotherapy-sensitive and potentially curable malignancies, which are treated with multimodality, dose-intensitive and neoadjuvant protocols regardless of size or overt metastatic disease. A limited number of effective agents available for the treatment of patients with metastatic adult soft-tissue sarcoma exists, which have failed anthracyline and ifosfamide-based chemotherapy. Read More

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Brostallicin, an agent with potential activity in metastatic soft tissue sarcoma: a phase II study from the European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group.

Eur J Cancer 2007 Jan 13;43(2):308-15. Epub 2006 Nov 13.

Department of Medical Oncology, Christie Hospital NHS Trust, Wilmslow Road, Manchester, M20 4BX, UK, and Erasmus University Medical Center, Rotterdam, Netherlands.

The study aimed to assess the efficacy and safety of brostallicin, a new DNA minor groove binder, at a dose of 10mg/m2, intravenous (i.v.) every three weeks, in patients with advanced or inoperable soft tissue sarcoma (STS) and gastrointestinal stromal tumour (GIST) failing first line therapy. Read More

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January 2007

Combination of thiol antioxidant Silibinin with Brostallicin is associated with increase in the anti-apoptotic protein Bcl-2 and decrease in caspase 3 activity.

Cancer Lett 2006 Jul 19;238(1):146-52. Epub 2005 Aug 19.

Department of Surgery, National University of Singapore, Singapore.

The cytotoxic activity of Brostallicin was previously shown to be enhanced in the presence of high glutathione and glutathione transferase levels. We hypothesized that thiol antioxidants, N-acetylcysteine and Silibinin, could potentiate Brostallicin's cytotoxicity in a similar way. HepG2 and CNE-2 cells were treated with N-acetylcysteine, Silibinin and Brostallicin, either alone or in combination. Read More

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Recent developments in salvage chemotherapy for patients with metastatic soft tissue sarcoma.

Drugs 2005 ;65(2):167-78

Medizinische Klinik II and Interdisciplinary Sarcoma Center, Universitätsklinikum, Eberhard-Karls-University, Tuebingen, Germany.

The number of effective cytotoxic agents for the treatment of patients with metastatic adult soft tissue sarcoma is limited, especially when patients have failed anthracycline- and ifosfamide-based chemotherapy. For the subgroup of patients with inoperable gastrointestinal stromal tumour (GIST), progress has been made via the rapid development and approval of the targeted therapy imatinib. Small round cell tumours (SRCTs), such as Ewing's sarcoma/primitive neuroectodermal tumour, desmoplastic SRCT and rhabdomyosarcoma, are chemotherapy-sensitive and potentially curable malignancies, which are treated with multimodality, dose-intensive, neoadjuvant protocols regardless of size or overt metastatic disease. Read More

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Cytotoxic alpha-halogenoacrylic derivatives of distamycin A and congeners.

J Med Chem 2004 May;47(10):2611-23

Pharmacia Italia S.p.A., Discovery Research Oncology, Viale Pasteur 10, 20014 Nerviano, Milan, Italy.

The mechanism of action of many antitumor agents involves DNA damage, either by direct binding of the drug to DNA or to DNA-binding proteins. However, most of the DNA-interacting agents have only a limited degree of sequence specificity, which implies that they may hit all the cellular genes. DNA minor groove binders, among which the derivatives of distamycin A play an important role, could provide significant improvement in cancer management, increasing gene specificity, due to high selectivity of interaction with thymine-adenine (TA) rich sequences. Read More

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Brostallicin: a new concept in minor groove DNA binder development.

Anticancer Drugs 2004 Jan;15(1):1-6

Laboratory of Molecular Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.

Brostallicin is a bromoacryloyl derivative of distamycin A, which has shown very promising preclinical activity against a variety of human tumors both in vitro and in vivo. The drug has a limited toxicity towards bone marrow precursor cells in vitro resulting in a therapeutic index much higher than those achieved with other distamycin A derivatives. It retains activity against cancer cells resistant to alkylating agents, topoisomerase I inhibitors and cells with mismatch repair deficiency. Read More

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January 2004

A phase I dose-escalation and pharmacokinetic study of brostallicin (PNU-166196A), a novel DNA minor groove binder, in adult patients with advanced solid tumors.

Clin Cancer Res 2004 Jan;10(2):468-75

Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA.

Purpose: This study was performed to determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetics of brostallicin, a nonalkylating DNA minor groove binder and a synthetic derivative of distamycin A, given as a weekly i.v. infusion. Read More

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January 2004

Enhancement of in vivo antitumor activity of classical anticancer agents by combination with the new, glutathione-interacting DNA minor groove-binder, brostallicin.

Clin Cancer Res 2003 Nov;9(14):5402-8

Laboratory of Molecular Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.

Purpose: Brostallicin (PNU-166196) is a alpha-bromoacrylic DNA minor groove binder, currently in clinical evaluation. This drug has the peculiarity of showing enhanced antitumor activity in cells with high glutathione S-transferase (GST)/glutathione content. The purpose of the study was to study multiple combinations of brostallicin with classical anticancer agents. Read More

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November 2003

Brostallicin (PNU-166196)--a new DNA minor groove binder that retains sensitivity in DNA mismatch repair-deficient tumour cells.

Br J Cancer 2003 Oct;89(8):1559-65

Department of Obstetrics and Gynaecology, Division of Gynaecology, University Hospital of Zurich, CH-8091, Switzerland.

Defects in DNA mismatch repair (MMR) are associated with a predisposition to tumorigenesis and with drug resistance owing to high mutation rates and failure to engage DNA-damage-induced apoptosis. DNA minor groove binders (MGBs) are a class of anticancer agents highly effective in a variety of human cancers. Owing to their mode of action, DNA MGB-induced DNA damage may be a substrate for DNA MMR. Read More

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October 2003

Phase I and pharmacokinetic study of brostallicin (PNU-166196), a new DNA minor-groove binder, administered intravenously every 3 weeks to adult patients with metastatic cancer.

Clin Cancer Res 2003 Aug;9(8):2957-64

Department of Medical Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam 3075 EA, the Netherlands.

Purpose: Brostallicin (PNU-166196) is a cytotoxic agent that binds to the minor groove of DNA with significant antitumor activity in preclinical studies. This trial was designed to determine the maximum tolerated dose, the toxicity profile, and the pharmacokinetics of Brostallicin in cancer patients.

Experimental Design: Patients were treated with escalating doses of Brostallicin ranging from 0. Read More

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LC-MS-MS determination of brostallicin in human plasma following automated on-line SPE.

J Pharm Biomed Anal 2003 Aug;32(4-5):601-7

Pharmacia Corp., Viale Pasteur 10, Nerviano, Milan 20014, Italy.

LC-MS-MS method using automated on-line solid-phase extraction (SPE) has been developed and validated for the quantitation of brostallicin (I), a new distamycin derivative, in human plasma. I is a DNA minor groove binder currently under phase I-II clinical evaluation as an anticancer drug. Plasma (0. Read More

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The discovery of a new potential anticancer drug: a case history.

Authors:
Paolo Cozzi

Farmaco 2003 Mar;58(3):213-20

Department of Chemistry, Pharmacia, Global Chemistry, Discovery Research Oncology, Viale Pasteur 10, 20014 Nerviano, Milan, Italy.

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. Read More

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Cytotoxic alpha-bromoacrylic derivatives of low molecular weight.

Bioorg Med Chem Lett 2002 Jun;12(11):1467-71

Chemistry Department, Pharmacia Discovery Research Oncology, Viale Pasteur 10, 20014 Nerviano, Milan, Italy.

In vitro and in vivo activities of a small series of alpha-bromoacrylic derivatives of low molecular weight (MW) are described and compared with those of alpha-bromoacrylic derivatives of distamycin-like frames. Low MW compounds, when lacking of a strong basic moiety, are potent cytotoxics, while analogues bearing a strong basic moiety are not. This suggests the existence of an active transport mechanism for distamycin-derived cytotoxics characterized by strong basic amidino or guanidino moieties. Read More

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Brostallicin, a novel anticancer agent whose activity is enhanced upon binding to glutathione.

Cancer Res 2002 Apr;62(8):2332-6

Laboratory of Molecular Pharmacology, Department of Oncology, Mario Negri Institute of Pharmacological Research, via Eritrea 62, 20157 Milan, Italy.

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. Read More

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Development of distamycin-related DNA binding anticancer drugs.

Expert Opin Investig Drugs 2001 Sep;10(9):1703-14

Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea, 62- 20157 Milan, Italy.

The relatively low therapeutic index of the clinically used alkylating agents is probably related to the fact that these compounds cause DNA damage in a relatively unspecific manner, mainly involving guanine-cytosine rich stretches of DNA present in virtually all genes, therefore inducing unselective growth inhibition and death, both in neoplastic and in highly proliferative normal tissues. These considerations explain why in the last twenty years there has been an increasing interest in the identification of compounds which can target DNA with a much higher degree of sequence specificity than that of conventional alkylators. Minor groove binders (MGBs) are one of the most widely studied class of alkylating agents characterised by a high level of sequence specificity. Read More

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September 2001
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