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

Caponigro, Francesco; Lorusso, Domenica; Fornari, Gianni; Barone, C.; Merlano, Marco; Airoldi, Mario; Schena, Marina; MacArthur, Robert B.; Weitman, Steven; Jannuzzo, M. G.; Crippa, Stefania; Fiorentini, F.; Petroccione, Anna; Comis, Silvia

doi:10.1007/s00280-009-1175-6

Cited by 9 publications

(4 citation statements)

References 8 publications

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“…34 When designing potential anti-cancer agents, non-intercalative platinum(II)-terpyridine complexes are largely overlooked in favor of metallo-intercalators. Given the success of groove binders such as Tallimustine 39,40 and Brostallicin 41,42 (both have undergone clinical trials) in cancer therapy, it is surprising that very few groove binding platinum(II)-terpyridine complexes have been reported. With the aim of exploring the ability of new metal complexes as DNA groove binders, we have prepared a platinum(II)-terpyridine complex (1) bearing two piperidine substituents at positions 2 and 2 0 (see Scheme 1).…”

Section: Introductionmentioning

confidence: 99%

A platinum complex that binds non-covalently to DNA and induces cell death via a different mechanism than cisplatin

et al. 2013

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Cisplatin and some of its derivatives have been shown to be very successful anticancer agents. Their main mode of action has been proposed to be via covalent binding to DNA. However, one of the limitations of these drugs is their poor activity against some tumours due to intrinsic or acquired resistance. Therefore, there is interest in developing complexes with different binding modes and mode of action. Herein we present a novel platinum(ii)-terpyridine complex (1) which interacts non-covalently with DNA and induces cell death via a different mechanism than cisplatin. The interaction of this complex with DNA was studied by UV/Vis spectroscopic titrations, fluorescent indicator displacement (FID) assays and circular dichroism (CD) titrations. In addition, computational docking studies were carried out with the aim of establishing the complex's binding mode. These experimental and computational studies showed the complex to have an affinity constant for DNA of ∼10(4) M(-1), a theoretical free energy of binding of -10.83 kcal mol(-1) and selectivity for the minor groove of DNA. Long-term studies indicated that 1 did not covalently bind (or nick) DNA. The cancer cell antiproliferative properties of this platinum(ii) complex were probed in vitro against human and murine cell lines. Encouragingly the platinum(ii) complex displayed selective toxicity for the cancerous (U2OS and SH-SY5Y) and proliferating NIH 3T3 cell lines. Further cell based studies were carried out to establish the mode of action. Cellular uptake studies demonstrated that the complex is able to penetrate the cell membrane and localize to the nucleus, implying that genomic DNA could be a cellular target. Detailed immunoblotting studies in combination with DNA-flow cytometry showed that the platinum(ii) complex induced cell death in a manner consistent with necrosis.

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Section: Introductionmentioning

confidence: 99%

A platinum complex that binds non-covalently to DNA and induces cell death via a different mechanism than cisplatin

et al. 2013

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“…For example, the agents cisplatin (CPT), ZEB, 5AZ, and brostallicin (BRC) are used in different combinations in chemotherapy (64)(65)(66). Specifically, BRC plus CPT is used to treat patients with advanced solid tumors (64), ZEB plus CPT has been used in human carcinoma cell lines (65), and ZEB plus BRC has been used in prostate cancer cell lines (66). We note that the ZEB plus 5AZ combination studied in this paper (Table 1) has been used successfully in mice with L1210 leukemia (20).…”

Section: Discussionmentioning

confidence: 99%

Mutagen Synergy: Hypermutability Generated by Specific Pairs of Base Analogs

et al. 2016

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We tested pairwise combinations of classical base analog mutagens in Escherichia coli to study possible mutagen synergies. We examined the cytidine analogs zebularine (ZEB) and 5-azacytidine (5AZ), the adenine analog 2-aminopurine (2AP), and the uridine/thymidine analog 5-bromodeoxyuridine (5BrdU). We detected a striking synergy with the 2AP plus ZEB combination, resulting in hypermutability, a 35-fold increase in mutation frequency (to 53,000 ؋ 10 ؊8 ) in the rpoB gene over that with either mutagen alone. A weak synergy was also detected with 2AP plus 5AZ and with 5BrdU plus ZEB. The pairing of 2AP and 5BrdU resulted in suppression, lowering the mutation frequency of 5BrdU alone by 6.5-fold. Sequencing the mutations from the 2AP plus ZEB combination showed the predominance of two new hot spots for A·T¡G·C transitions that are not well represented in either single mutagen spectrum, and one of which is not found even in the spectrum of a mismatch repair-deficient strain. The strong synergy between 2AP and ZEB could be explained by changes in the dinucleoside triphosphate (dNTP) pools. IMPORTANCEAlthough mutagens have been widely studied, the mutagenic effects of combinations of mutagens have not been fully researched. Here, we show that certain pairwise combinations of base analog mutagens display synergy or suppression. In particular, the combination of 2-aminopurine and zebularine, analogs of adenine and cytidine, respectively, shows a 35-fold increased mutation frequency compared with that of either mutagen alone. Understanding the mechanism of synergy can lead to increased understanding of mutagenic processes. As combinations of base analogs are used in certain chemotherapy regimens, including those involving ZEB and 5AZ, these results indicate that testing the mutagenicity of all drug combinations is prudent. Mutagen-induced mutations have been the subject of intensive investigation for decades (e.g., see references 1 to 4; see reviews in references 5 to 7). However, there are far fewer studies of combinations of mutagens. We are studying possible synergies between mutagens in Escherichia coli and initially examined a set of base analog mutagens ( Fig. 1): the cytidine analogs zebularine (ZEB) and 5-azacytidine (5AZ), the adenine analog 2-aminopurine (2AP), and the uridine/thymidine analog 5-bromodeoxyuridine (5BrdU). ZEB lacks the amino group of cytidine (8) and causes C·G¡T·A changes in the rpoB/rifampin resistance (Rif r ) system in E. coli (9). It is used in chemotherapy as a demethylating agent (8, 10, 11) to reverse the effects of gene-silenced tumor suppressor gene (12-15) and because the hydrated form is a potent inhibitor of cytidine deaminase (16). 5AZ, another cytidine analog that is used as a demethylating agent in chemotherapy (12, 13), possesses a unique mutagenic specificity, stimulating only C·G¡G·C changes (17-19). 5AZ and ZEB have been used in combination in chemotherapy (20). 2-Aminopurine results principally in G·C¡A·T and A·T¡G·C changes (e.g., see references 18 and 21 to 25), as...

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“…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. Others agents examined in early phase analysis have shown some activity in HER2-positive and BRCA1/2 mutation-associated breast cancer, but not particular efficacy in unselected TNBC [68].…”

Section: Minor Groove Bindersmentioning

confidence: 99%

Treatment of Metastatic Triple-Negative Breast Cancer

Glendenning

Irshad

Tutt

2012

Curr Breast Cancer Rep

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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.

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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

Abstract: International audienc

Cited by 9 publications

References 8 publications

A platinum complex that binds non-covalently to DNA and induces cell death via a different mechanism than cisplatin

A platinum complex that binds non-covalently to DNA and induces cell death via a different mechanism than cisplatin

Mutagen Synergy: Hypermutability Generated by Specific Pairs of Base Analogs

Treatment of Metastatic Triple-Negative Breast Cancer

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