Toxicity of intracranial and intraperitoneal O6-benzyl guanine in combination with BCNU delivered locally in a mouse model

Guarnieri, Michael; Biser-Rohrbaugh, Ann; Tyler, Betty; Gabikian, Patrik; Bunton, Tracie E.; Wu, Qing Ze; Weingart, Jon; Carson, Benjamin S.

doi:10.1007/s00280-002-0510-y

Cited by 8 publications

(7 citation statements)

References 11 publications

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“…These alkylation adducts can form upon exposure of guanine to many different compounds. For example, Me-dG and POB-dG can result from a tobacco carcinogen that has been linked to lung cancer. − Additionally, synthetic alkylation adducts, such as Bz-dG, have been developed as inhibitors for O6-alkylguanine-DNA alkyltransferase for cancer treatment but are carcinogenic to patients who survive for the long term. , …”

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confidence: 99%

“…4−8 Additionally, synthetic alkylation adducts, such as Bz-dG, have been developed as inhibitors for O6-alkylguanine-DNA alkyltransferase for cancer treatment but are carcinogenic to patients who survive for the long term. 9,10 The propensity of O6-dG alkylation adducts to cause cancer stems from their effects on DNA replication, specifically their tendency to form base mispairs. In general, such genetic mutations occur because the standard DNA replication pathway is impeded or completely blocked by bulky adducts.…”

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confidence: 99%

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Molecular Insights into the Translesion Synthesis of Benzyl-Guanine from Molecular Dynamics Simulations: Structural Evidence of Mutagenic and Nonmutagenic Replication

Wilson

Wetmore

2017

Biochemistry

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DNA can be damaged by many compounds in our environment, and the resulting damaged DNA is commonly replicated by translesion synthesis (TLS) polymerases. Because the mechanism and efficiency of TLS are affected by the type of DNA damage, obtaining information for a variety of DNA adducts is critical. However, there is no structural information for the insertion of a dNTP opposite an O6-dG adduct, which is a particularly harmful class of DNA lesions. We used molecular dynamics (MD) simulations to investigate structural and energetic parameters that dictate preferred dNTP insertion opposite O6-benzyl-guanine (Bz-dG) by DNA polymerase IV, a prototypical TLS polymerase. Specifically, MD simulations were completed on all possible ternary insertion complexes and ternary -1 base deletion complexes with different Bz-dG conformations. Our data suggests that the purines are unlikely to be inserted opposite anti- or syn-Bz-dG, and dTTP is unlikely to be inserted opposite syn-Bz-dG, because of changes in the active site conformation, including critical hydrogen-bonding interactions and/or reaction-ready parameters compared to natural dG replication. In contrast, a preserved active site conformation suggests that dCTP can be inserted opposite either anti- or syn-Bz-dG and dTTP can be inserted opposite anti-Bz-dG. This is the first structural explanation for the experimentally observed preferential insertion of dCTP and misincorporation of dTTP opposite Bz-dG. Furthermore, we provide atomic level insight into why Bz-dG replication does not lead to deletion mutations, which is in contrast with the replication outcomes of other adducts. These findings provide a basis for understanding the replication of related O6-dG adducts.

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confidence: 99%

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confidence: 99%

Molecular Insights into the Translesion Synthesis of Benzyl-Guanine from Molecular Dynamics Simulations: Structural Evidence of Mutagenic and Nonmutagenic Replication

Wilson

Wetmore

2017

Biochemistry

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“…Osmotic minipumps are commonly used in the laboratory to deliver drugs at a constant rate to animals [41][42][43][44] and they have no adverse effect on rat development or behavior [45]. A stepmotor micropump for the injection of nanoliter volumes of D-amphetamine solution into discrete brain regions of freely moving rats delivered a reliable volume of 50 nl per infusion over an hour at a rate of one infusion per minute [46].…”

Section: Micropumpsmentioning

confidence: 99%

An Integrated Platform for Bio-Analysis and Drug Delivery

Amer¹,

Badawy

2005

CPB

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The advances in the microelectronics fabrication allow the strong appearance of micro-electro-mechanical systems known as MEMS. MEMS enable the fabrication of smaller devices that are manufactured using standard micro-fabrication techniques similar to the ones that are used to create computer silicon chips. Several MEMS devices including micro-reservoirs, micro-pumps, cantilevers, rotors, channels, valves, sensors, and other structures have been designed, fabricated and tested from using materials that have been demonstrated to be biocompatible. This paper reviews the status of Micro-electronic and MEMS systems that can be used for adaptive drug administration. It presents different components and describes a possible implementation. Finally it presents a prototype that is termed ipill which stands intelligent pill.

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“…Standard surgical techniques, which have been previously described, were used for implanting the tumor cells, pumps, and infusion catheters (Carson et al, 2002;Guarnieri et al, 2002;Wu et al, 2002). Briefly, rats were anesthetized with 0.65 mL of a solution containing 25 mg/mL ketamine hydrochloride, 2.5 mg/mL xylazine, and 14.25% ethyl alcohol in saline.…”

Section: Surgerymentioning

confidence: 99%

Flexible versus rigid catheters for chronic administration of exogenous agents into central nervous system tissues

Guarnieri¹,

Carson²,

Khan³

et al. 2005

Journal of Neuroscience Methods

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Toxicity of intracranial and intraperitoneal O6-benzyl guanine in combination with BCNU delivered locally in a mouse model

Abstract: Based on the results of this study, a dose escalation study will be necessary when combining systemic O6BG with the higher doses of i.c. BCNU.

Cited by 8 publications

References 11 publications

Molecular Insights into the Translesion Synthesis of Benzyl-Guanine from Molecular Dynamics Simulations: Structural Evidence of Mutagenic and Nonmutagenic Replication

Molecular Insights into the Translesion Synthesis of Benzyl-Guanine from Molecular Dynamics Simulations: Structural Evidence of Mutagenic and Nonmutagenic Replication

An Integrated Platform for Bio-Analysis and Drug Delivery

Flexible versus rigid catheters for chronic administration of exogenous agents into central nervous system tissues

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