BNP7787-Mediated Modulation of Paclitaxel- and Cisplatin-Induced Aberrant Microtubule Protein Polymerization <i>In vitro</i>

Parker, Aulma R.; Petluru, Pavankumar N.; Wu, Mei‐Zhen; Zhao, Min; Kochat, Harry; Hausheer, Frederick H.

doi:10.1158/1535-7163.mct-10-0300

Cited by 10 publications

(7 citation statements)

References 40 publications

(80 reference statements)

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“…Some clinical data, with different levels of reliability (Table 3), indicated that amifostine exerts some protection against peripheral neurotoxicity of carboplatin plus paclitaxel combination therapy [127][128][129]131], oxaliplatin [126], and cisplatin [133,134], whereas two other studies have failed to show significant neuroprotection against carboplatin plus paclitaxel combination therapy [130] and cisplatin [132] (Table 3). BNP7787 (Dimesna, Tavocept, 2,29-dithio-bis-ethanesulfonate) has also shown some cytoprotective activities in vitro [174]. This effect was not confirmed in the clinical setting, although the study was unblinded with no placebo-controlled group and high risk of bias [135].…”

Section: Detoxicantsmentioning

confidence: 99%

Platinum-Induced Neurotoxicity and Preventive Strategies: Past, Present, and Future

et al. 2015

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Neurotoxicity is a burdensome side effect of platinum-based chemotherapy that prevents administration of the full efficacious dosage and often leads to treatment withdrawal. Peripheral sensory neurotoxicity varies from paresthesia in fingers to ataxic gait, which might be transient or irreversible. Because the number of patients being treated with these neurotoxic agents is still increasing, the need for understanding the pathogenesis of this dramatic side effect is critical. Platinum derivatives, such as cisplatin and carboplatin, harm mainly peripheral nerves and dorsal root ganglia neurons, possibly because of progressive DNA-adduct accumulation and inhibition of DNA repair pathways (e.g., extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase/stressactivated protein kinase, and p38 mitogen-activated protein kinass), which finally mediate apoptosis. Oxaliplatin, with a completely different pharmacokinetic profile, may also alter calcium-sensitive voltage-gated sodium channel kinetics through a calcium ion immobilization by oxalate residue as a calcium chelator and cause acute neurotoxicity. Polymorphisms in several genes, such as voltage-gated sodium channel genes or genes affecting the activity of pivotal metal transporters (e.g., organic cation transporters, organic cation/carnitine transporters, and some metal transporters, such as the copper transporters, and multidrug resistance-associated proteins), can also influence drug neurotoxicity and treatment response. However, most pharmacogenetics studies need to be elucidated by robust evidence. There are supportive reports about the effectiveness of several neuroprotective agents (e.g., vitamin E, glutathione, amifostine, xaliproden, and venlafaxine), but dose adjustment and/or drug withdrawal seem to be the most frequently used methods in the management of platinuminducedperipheral neurotoxicity.Todevelopalternative optionsin the treatment of platinum-induced neuropathy, studies on in vitro models and appropriate trials planning should be integrated into the future design of neuroprotective strategies to find the best patient-oriented solution. The Oncologist 2015;20:411-432 Implications for Practice: Neurotoxicity is a burdensome side effect of platinum-based chemotherapy that prevents administration of the full efficacious dosage and often leads to treatment withdrawal. This review summarizes preclinical and clinical evidence of pathogenesis and pathophysiology of platinum-induced peripheral neurotoxicity, as well as available evidence of neuroprotective and therapeutic strategies. These data may help to develop alternative options in the treatment of platinuminduced neuropathy, studies on in vitro models, and appropriate trials planning to find the best patient-oriented solution.

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Section: Detoxicantsmentioning

confidence: 99%

Platinum-Induced Neurotoxicity and Preventive Strategies: Past, Present, and Future

et al. 2015

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“…BNP7787 is expected to remain predominantly in the disulfide form in the plasma; 6 , 10 , 32 however, the intracellular environment and the interstitial space are likely venues for BNP7787 metabolism to mesna, mesna-disulfide heteroconjugates, and free thiols. Any of these species (BNP7787, intracellularly generated BNP7787-derived mesna, or BNP7787-derived mesna-disulfide heteroconjugates) may modify proteins in vivo.…”

Section: Discussionmentioning

confidence: 99%

Novel covalent modification of human anaplastic lymphoma kinase (ALK) and potentiation of crizotinib-mediated inhibition of ALK activity by BNP7787

Parker

Petluru

Nienaber³

et al. 2015

OTT

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BNP7787 (Tavocept, disodium 2,2′-dithio-bis-ethanesulfonate) is a novel, investigational, water-soluble disulfide that is well-tolerated and nontoxic. In separate randomized multicenter Phase II and Phase III clinical trials in non-small-cell lung cancer (NSCLC) patients, treatment with BNP7787 in combination with standard chemotherapy resulted in substantial increases in the overall survival of patients with advanced adenocarcinoma of the lung in the first-line treatment setting. We hypothesized that BNP7787 might interact with and modify human anaplastic lymphoma kinase (ALK). At least seven different variants of ALK fusions with the gene encoding the echinoderm microtubule-associated protein-like 4 (EML4) are known to occur in NSCLC. EML4–ALK fusions are thought to account for approximately 3% of NSCLC cases. Herein, we report the covalent modification of the kinase domain of human ALK by a BNP7787-derived mesna moiety and the functional consequences of this modification in ALK assays evaluating kinase activity. The kinase domain of the ALK protein crystallizes as a monomer, and BNP7787-derived mesna-cysteine adducts were observed at Cys 1235 and Cys 1156. The BNP7787-derived mesna adduct at Cys 1156 is located in close proximity to the active site and results in substantial disorder of the P-loop and activation loop (A-loop). Comparison with the P-loop of apo-ALK suggests that the BNP7787-derived mesna adduct at Cys 1156 interferes with the positioning of Phe 1127 into a small pocket now occupied by mesna, resulting in a destabilization of the loop’s binding orientation. Additionally, in vitro kinase activity assays indicate that BNP7787 inhibits ALK catalytic activity and potentiates the activity of the ALK-targeted drug crizotinib.

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“…The mechanism of action, safety, effectiveness, and potential for tumour protection of this agent have been extensively evaluated using in vitro and in vivo models (Parker et al, 2010).…”

Section: Tavocept (Disodium 22´-dithiobisethane Sulfonate Bnp7787 mentioning

confidence: 99%

Neuropathy Secondary to Chemotherapy: A Real Issue for Cancer Survivors

Cidon¹

2012

Basic Principles of Peripheral Nerve Disorders

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BNP7787-Mediated Modulation of Paclitaxel- and Cisplatin-Induced Aberrant Microtubule Protein Polymerization In vitro

Cited by 10 publications

References 40 publications

Platinum-Induced Neurotoxicity and Preventive Strategies: Past, Present, and Future

Platinum-Induced Neurotoxicity and Preventive Strategies: Past, Present, and Future

Novel covalent modification of human anaplastic lymphoma kinase (ALK) and potentiation of crizotinib-mediated inhibition of ALK activity by BNP7787

Neuropathy Secondary to Chemotherapy: A Real Issue for Cancer Survivors

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