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

Lorusso, Domenica; Mainenti, S.; Pietragalla, Antonella; Ferrandina, Gabriella; Foco, Gilda; Masciullo, Valeria; Scambia, Giovanni

doi:10.1517/13543780903401284

Cited by 26 publications

(15 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There is a suggestion that high concentrations of GSH, GSH-Px and GSTpi, independent of other intracellular alterations, do not decisively contribute to MDR [19,20]. …”

Section: Discussionmentioning

confidence: 99%

Expression of glutathione, glutathione peroxidase and glutathione S-transferase pi in canine mammary tumors

et al. 2014

View full text Add to dashboard Cite

BackgroundGlutathione (GSH) is one of the most important agents of the antioxidant defense system of the cell because, in conjunction with the enzymes glutathione peroxidase (GSH-Px) and glutathione S transferase pi (GSTpi), it plays a central role in the detoxification and biotransformation of chemotherapeutic drugs. This study evaluated the expression of GSH and the GSH-Px and GSTpi enzymes by immunohistochemistry in 30 canine mammary tumors, relating the clinicopathological parameters, clinical outcome and survival of the bitches. In an in vitro study, the expression of the genes glutamate cysteine ligase (GCLC) and glutathione synthetase (GSS) that synthesize GSH and GSH-Px gene were verified by qPCR and subjected to treatment with doxorubicin, to check the resistance of cancer cells to chemotherapy.ResultsThe immunohistochemical expression of GSH, GSH-Px and GSTpi was compared with the clinical and pathological characteristics and the clinical outcome in the bitches, including metastasis and death.The results showed that high immunoexpression of GSH was correlated to the absence of tumor ulceration and was present in dogs without metastasis (P < 0.05). There was significant correlation of survival with the increase of GSH (P < 0.05). The expression of the GSH-Px and GSTpi enzymes showed no statistically significant correlation with the analyzed variables (p > 0.05). The analysis of the relative expression of genes responsible for the synthesis of GSH (GCLC and GSS) and GSH-Px by quantitative PCR was done with cultured cells of 10 tumor fragments from dogs with mammary tumors.The culture cells showed a decrease in GCLC and GSS expression when compared with no treated cells (P < 0.05). High GSH immunoexpression was associated with better clinical outcomes.ConclusionTherefore, high expression of the GSH seems to play an important role in the clinical outcome of patients with mammary tumors and suggest its use as prognostic marker. The in vitro doxorubicin treatment significantly reduces the expression of GCLC and GSS genes so we can consider them to be candidates for predictive markers of therapeutic response in mammary cancer.

show abstract

“…There is a suggestion that high concentrations of GSH, GSH-Px and GSTpi, independent of other intracellular alterations, do not decisively contribute to MDR [19,20]. …”

Section: Discussionmentioning

confidence: 99%

Expression of glutathione, glutathione peroxidase and glutathione S-transferase pi in canine mammary tumors

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Moreover, brostallicin, a second-generation MGB, has been reported to retain sensitivity in chemo-resistant DNA mismatch repair-deficient cells [60][61][62] and demonstrated synergy in combination with cisplatin [63][64][65], suggesting its potential value in cancer treatment. Its unique mechanism of action and the promising results from phase 1 and phase 2 clinical trials [65][66][67] involving more than 230 patients led to a phase 2 study of brostallicin (NCT01091454, currently suspended) in combination with cisplatin in patients with refractory metastatic TNBC.…”

Section: Minor Groove Bindersmentioning

confidence: 99%

Treatment of Metastatic Triple-Negative Breast Cancer

Glendenning

Irshad

Tutt

2012

Curr Breast Cancer Rep

View full text Add to dashboard Cite

The triple-negative breast cancer (TNBC) phenotype, defined as the lack of estrogen and progesterone hormone receptors and the HER2 receptor, represents approximately 15% to 20% of all breast cancer cases. Challenges faced in management of these patients arise from the heterogeneity of TNBC and the absence of well-defined molecular targets. Subgroups derive significant benefit from cytotoxics however, patients with TNBC have higher rates of distant recurrence and a poorer prognosis than women with other breast cancer subtypes overall. Currently, cytotoxic chemotherapy is the only systemic treatment option at all stages of disease, and rational drug selection based on tumor biology remains an aspiration. In the context of relapse, the most efficacious regimens remain undefined and the typical clinical picture is one of rapid disease progression and little durable benefit to therapy. This article reviews current approaches in metastatic TNBC and considers novel therapies in development that may improve the outlook for those with this disease.

show abstract

“…The α-bromoacryloyl moiety is present in a series of potent anticancer distamycin-like minor groove binders, including PNU-166196 (brostallicin, 3 ), which was evaluated as a first-line single agent chemotherapy in patients with advanced or metastatic soft tissue sarcoma [22,23]. It has been hypothesized that the reactivity of the α-bromoacryoyl moiety results from a first-step Michael-type nucleophilic attack, followed by a further reaction of the former vinylic bromo substituent alpha to the carbonyl, leading successively either to a second nucleophilic substitution or to a beta elimination [24].…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and biological evaluation of arylcinnamide hybrid derivatives as novel anticancer agents

Romagnoli

Baraldi

Salvador

et al. 2014

European Journal of Medicinal Chemistry

View full text Add to dashboard Cite

The combination of two pharmacophores into a single molecule represents one of the methods that can be adopted for the synthesis of new anticancer molecules. A series of novel antiproliferative agents designed by a pharmacophore hybridization approach, combining the arylcinnamide skeleton and an α-bromoacryloyl moiety, was synthesized and evaluated for its antiproliferative activity against a panel of seven human cancer cell lines. In addition, the new derivatives were also active on multidrug-resistant cell lines over-expressing P-glycoprotein. The biological effects of various substituents on the N-phenyl ring of the benzamide portion were also described. In order to study the possible mechanism of action, we observed that 4p slightly increased the Reactive Oxygen Species (ROS) production in HeLa cells, but, more importantly, a remarkable decrease of intracellular reduced glutathione content was detected in treated cells compared with controls. These results were confirmed by the observation that only thiol-containing antioxidants were able to significantly protect the cells from induced cell death. Altogether our results indicate that the new derivatives are endowed with good anticancer activity in vitro, and their properties may result in the development of new cancer therapeutic strategies.

show abstract

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

Cited by 26 publications

References 26 publications

Expression of glutathione, glutathione peroxidase and glutathione S-transferase pi in canine mammary tumors

Expression of glutathione, glutathione peroxidase and glutathione S-transferase pi in canine mammary tumors

Treatment of Metastatic Triple-Negative Breast Cancer

Design, synthesis and biological evaluation of arylcinnamide hybrid derivatives as novel anticancer agents

Contact Info

Product

Resources

About