Phase I Study of O<sup>6</sup>-Benzylguanine and Temozolomide Administered Daily for 5 Days to Pediatric Patients With Solid Tumors

Warren, Katherine E.; Aikin, Alberta; Libucha, Madeleine; Widemann, Brigitte C.; Fox, Elizabeth; Packer, Roger J.; Balis, Frank M.

doi:10.1200/jco.2005.02.0024

Cited by 44 publications

(45 citation statements)

References 39 publications

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“…Notably in this study, the use of 6-BG in concert with TMZ caused no significant collateral toxicity in extra-hematopoietic tissues. This observation correlates with results obtained in clinical trials [ 91,92 ].…”

Section: Chemoselection and Stem Cell Biologysupporting

confidence: 80%

Live and let die: In vivo selection of gene-modified hematopoietic stem cells via MGMT-mediated chemoprotection

Milsom

Williams

2007

DNA Repair

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Gene transfer into hematopoietic stem cells (HSC) provides a potential means of correcting monogenic defects and altering drug sensitivity of normal bone marrow to cytotoxic agents. These applications have significant therapeutic potential but the translation of successful murine studies into human therapies has been hindered by low gene transfer in large animals (including humans), and recent serious side effects in a human immunodeficiency trial related to insertional mutagenesis. The latter trial, along with other subsequent trials, while bringing into focus the potential risks of integrating vector systems, also clearly demonstrate the potential usefulness of in vivo selection as it relates to inefficient stem cell transduction. Developing from initial studies by our group and other investigators in which drug resistance was utilized to demonstrate the feasibility of using gene transfer to effect protection from myelotoxicity of chemotherapeutic agents, expression of mutant forms of O 6 -methyguanine-DNA-methytransferase (MGMT) coupled with the simultaneous use of pharmacologic inhibitors and chemotherapeutic agents has been shown to provide a powerful method to select HSC in vivo. While stem and progenitor cell protection and resulting selection in vivo has potential applications for the treatment of selected cancers (allowing dose escalation) andor correction of monogenic disease (allowing an iatrogenic survival advantage of transduced cells in vivo), such an in vivo selection may have untoward effects on stem cell behavior. These deleterious effects may include stem cell exhaustion; lineage skewing; accumulation of genotoxic lesions; and clonal dominance driven towards a pro-leukemic phenotype. Knowledge of the likelihood of such deleterious events occurring as well as their potential implications will be critical to future clinical applications and may also enhance our understanding of both normal stem cell behavior and the evolution of hematopoietic malignancies.

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Section: Chemoselection and Stem Cell Biologysupporting

confidence: 80%

Live and let die: In vivo selection of gene-modified hematopoietic stem cells via MGMT-mediated chemoprotection

Milsom

Williams

2007

DNA Repair

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“…A combination of Bg with alkylating agents, improved the efficacy of glioma treatment and other solid tumors considering its toxic limitations. 30,31 hMutSalpha is probably the main 6-TG repair enzyme through recognition of 6-methylthioguanine. 32 MGMT is probably not the main repair enzyme for 6-TG damage but based on our evidence it has an important role.…”

Section: Methodsmentioning

confidence: 99%

Acquired resistance to 6-thioguanine in melanoma cells involves the repair enzyme O⁶- methylguanine-DNA methyltransferase (MGMT).

Gefen¹,

Brkic²,

Galron³

et al. 2010

Cancer Biology & Therapy

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“…Plasmids for the production of N-terminal His 6 -tagged W65C and K178R of hAGT were constructed from the template plasmids of pQE30-hAGT [38] with Quick Change Site-directed Mutagenesis Kit used according to the manufacturer's instructions. Primers W65C-P1: All of the N-terminal His 6 -tagged hAGT proteins differ from the wild type by the addition of a terminal MRGS(H) 6 GS-to the protein [38]. The C-terminal His 6 -tagged hAGT have a (His) 6 sequence replacing residues 202−207 [37].…”

Section: Construction Of Pqe Plasmids For Expression Of Different Hagmentioning

confidence: 99%

“…Primers W65C-P1: All of the N-terminal His 6 -tagged hAGT proteins differ from the wild type by the addition of a terminal MRGS(H) 6 GS-to the protein [38]. The C-terminal His 6 -tagged hAGT have a (His) 6 sequence replacing residues 202−207 [37].…”

Section: Construction Of Pqe Plasmids For Expression Of Different Hagmentioning

confidence: 99%

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Differential inactivation of polymorphic variants of human O6-alkylguanine-DNA alkyltransferase

Fang

Loktionova

Moschel

et al. 2008

Biochemical Pharmacology

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The human DNA repair protein O 6 -alkylguanine-DNA alkyltransferase (hAGT) is an important source of resistance to some therapeutic alkylating agents and attempts to circumvent this resistance by the use of hAGT inhibitors have reached clinical trials. Several human polymorphisms in the MGMT gene that encodes hAGT have been described including L84F and the linked double alteration I143V/K178R. We have investigated the inactivation of these variants and the much rarer variant W65C by O 6 -benzylguanine, which is currently in clinical trials, and a number of other second generation hAGT inhibitors that contain folate derivatives (O 4 -benzylfolic acid, the 3' and 5' folate esters of O 6 -benzyl-2'-deoxyguanosine and the folic acid γ ester of O 6 -(p-hydroxymethyl) benzylguanine). The I143V/K178R variant was resistant to all of these compounds. The resistance was due solely to the I143V change. These results suggest that the frequency of the I143V/K178R variant among patients in the clinical trials with hAGT inhibitors and the correlation with response should be considered.

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Phase I Study of O⁶-Benzylguanine and Temozolomide Administered Daily for 5 Days to Pediatric Patients With Solid Tumors

Abstract: The recommended doses of O6BG administered with TMZ on a 5-day schedule in children are 120 mg/m2/d of O6BG and 75 mg/m2/d of TMZ. Evidence of activity was observed at these doses. Myelosuppression was the DLT.

Cited by 44 publications

References 39 publications

Live and let die: In vivo selection of gene-modified hematopoietic stem cells via MGMT-mediated chemoprotection

Live and let die: In vivo selection of gene-modified hematopoietic stem cells via MGMT-mediated chemoprotection

Acquired resistance to 6-thioguanine in melanoma cells involves the repair enzyme O⁶- methylguanine-DNA methyltransferase (MGMT).

Differential inactivation of polymorphic variants of human O6-alkylguanine-DNA alkyltransferase

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Phase I Study of O6-Benzylguanine and Temozolomide Administered Daily for 5 Days to Pediatric Patients With Solid Tumors

Abstract: The recommended doses of O6BG administered with TMZ on a 5-day schedule in children are 120 mg/m2/d of O6BG and 75 mg/m2/d of TMZ. Evidence of activity was observed at these doses. Myelosuppression was the DLT.

Cited by 44 publications

References 39 publications

Live and let die: In vivo selection of gene-modified hematopoietic stem cells via MGMT-mediated chemoprotection

Live and let die: In vivo selection of gene-modified hematopoietic stem cells via MGMT-mediated chemoprotection

Acquired resistance to 6-thioguanine in melanoma cells involves the repair enzyme O6- methylguanine-DNA methyltransferase (MGMT).

Differential inactivation of polymorphic variants of human O6-alkylguanine-DNA alkyltransferase

Contact Info

Product

Resources

About

Phase I Study of O⁶-Benzylguanine and Temozolomide Administered Daily for 5 Days to Pediatric Patients With Solid Tumors

Acquired resistance to 6-thioguanine in melanoma cells involves the repair enzyme O⁶- methylguanine-DNA methyltransferase (MGMT).