Brain Tumor Treatment: Significant Contributions

Blaese, R. Michael; CULVER, K.; Ishii, Hiroki; Oldfield, E H; Ram, Zvi; Wallbridge, S.

doi:10.1126/science.1470923

Cited by 4 publications

(2 citation statements)

References 2 publications

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“…Prodrug 1, and the activated drug 1a ( Figure 1) were synthesized as previously described (14). The prodrug analog 4-[bis(2hydroxyethyl)amino]-3,5-difluorobenzoyl-L-glutamic acid (2) was synthesized in two steps from the previously described 4-(bis(2-hydroxyethyl)amino)-3,5-difluorobenzoic acid (2a) (15). NMR spectra were determined in Me 2 SO-d 6 using TMS or CFCl 3 as internal standards on a Bruker Avance 250 spectrometer at 258C.…”

Section: Synthesis Of Compoundsmentioning

confidence: 99%

“…The effective use of anticancer therapies is often limited by their toxicity to normal tissues. Suicide gene therapy or GDEPT (Gene-directed enzyme prodrug therapy; (1)(2)(3)(4)(5)(6)) is designed to overcome this problem by administering a nontoxic prodrug that is activated only at the site of tumor. This selective activation is achieved by first transducing the tumor cells with a gene for the specific exogenous enzyme required for prodrug conversion.…”

Section: Introductionmentioning

confidence: 99%

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A novel technique to monitor carboxypeptidase G2 expression in suicide gene therapy using ¹⁹F magnetic resonance spectroscopy

et al. 2009

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Development and evaluation of new anticancer drugs are expedited when minimally invasive biomarkers of pharmacokinetic and pharmacodynamic behaviour are available. Gene-directed enzyme prodrug therapy (GDEPT) is a suicide gene therapy in which the anticancer drug is activated in the tumor by an exogenous enzyme previously targeted by a vector carrying the gene. GDEPT has been evaluated in various clinical trials using several enzyme/prodrug combinations. The key processes to be monitored in GDEPT are gene delivery and expression, as well as prodrug delivery and activation. {4-[bis(2-chloroethyl)amino]-3,5-difluorobenzoyl}-L-glutamic acid, a prodrug for the GDEPT enzyme carboxypeptidase-G2 (CPG2; K(m) = 1.71 microM; k(cat) = 732 s(-1)), was measured with (19)F magnetic resonance spectroscopy (MRS). The 1 ppm chemical shift separation found between the signals of prodrug and activated drug (4-[bis(2-chloroethyl)amino]-3,5-difluorobenzoic acid) is sufficient for the detection of prodrug activation in vivo. However, these compounds hydrolyze rapidly, and protein binding broadens the MR signals. A new CPG2 substrate was designed with hydroxyethyl instead of chloroethyl groups (K(m) = 3.5 microM, k(cat) = 747 s(-1)). This substrate is nontoxic and stable in solution, has a narrow MRS resonance in the presence of bovine and foetal bovine albumin, and exhibits a 1.1 ppm change in chemical shift upon cleavage by CPG2. In cells transfected to express CPG2 in the cytoplasm (MDA MB 361 breast carcinoma cells and WiDr colon cancer cells), well-resolved (19)F MRS signals were observed from clinically relevant concentrations of the new substrate and its nontoxic product. The MRS conversion half-life (470 min) agreed with that measured by HPLC (500 min). This substrate is, therefore, suitable for evaluating gene delivery and expression prior to administration of the therapeutic agent.

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Section: Synthesis Of Compoundsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A novel technique to monitor carboxypeptidase G2 expression in suicide gene therapy using ¹⁹F magnetic resonance spectroscopy

et al. 2009

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Gene therapy for pancreatic cancer

Takeda

Nakao

Miyoshi

1998

Semin. Surg. Oncol.

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It has been approximately 7 years since the introduction of gene therapy. Since conventional procedures such as surgery, chemotherapy, and radiotherapy have had limited therapeutic value for cancer patients, the evolution of gene therapy seems a promising alternative to many researchers and clinicians. Indeed, about half of all gene therapy treatments are administered to patients with cancer. However, there are relatively few studies of using gene therapy with pancreatic cancer. We will review the general concept of gene therapy for cancer and its accomplishments to date. Semin. Surg. Oncol. 15:57–61, 1998. © 1998 Wiley‐Liss, Inc.

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AV.TK-mediated killing of subcutaneous tumors in situ results in effective immunization against established secondary intracranial tumor deposits

et al. 2001

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Gene transfer vectors expressing herpes simplex thymidine kinase (HSVtk), in addition to direct killing of tumor cells, often have an associated local 'bystander effect' mediated by metabolic coupling of tumor cells. A systemic antitumor effect mediated by the immune system, termed the distant bystander effect, has also been reported. We have observed the development of cytotoxic T-lymphocyte (CTL) popu-

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Brain Tumor Treatment: Significant Contributions

Abstract: Arc lamps in mercury and xenon burners work under high vacuum and high temperatures. These safety steps are highly recommended.

Cited by 4 publications

References 2 publications

A novel technique to monitor carboxypeptidase G2 expression in suicide gene therapy using ¹⁹F magnetic resonance spectroscopy

A novel technique to monitor carboxypeptidase G2 expression in suicide gene therapy using ¹⁹F magnetic resonance spectroscopy

Gene therapy for pancreatic cancer

AV.TK-mediated killing of subcutaneous tumors in situ results in effective immunization against established secondary intracranial tumor deposits

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Brain Tumor Treatment: Significant Contributions

Abstract: Arc lamps in mercury and xenon burners work under high vacuum and high temperatures. These safety steps are highly recommended.

Cited by 4 publications

References 2 publications

A novel technique to monitor carboxypeptidase G2 expression in suicide gene therapy using 19F magnetic resonance spectroscopy

A novel technique to monitor carboxypeptidase G2 expression in suicide gene therapy using 19F magnetic resonance spectroscopy

Gene therapy for pancreatic cancer

AV.TK-mediated killing of subcutaneous tumors in situ results in effective immunization against established secondary intracranial tumor deposits

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Product

Resources

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A novel technique to monitor carboxypeptidase G2 expression in suicide gene therapy using ¹⁹F magnetic resonance spectroscopy

A novel technique to monitor carboxypeptidase G2 expression in suicide gene therapy using ¹⁹F magnetic resonance spectroscopy