Gene-directed enzyme prodrug therapy (GDEPT): choice of prodrugs

Cj, Springer; Niculescu‐Duvaz, Ion

doi:10.1016/s0169-409x(96)00449-8

Cited by 44 publications

(22 citation statements)

References 18 publications

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“…Several novel gene-based treatments for cancer have been introduced over the past few years. In one approach, genes encoding prodrug-activation enzymes are used as "suicide" genes to sensitize tumor cells to drugs that are otherwise not cytotoxic (Springer and Niculescu-Duvaz, 1996). This strategy, referred to as GDEPT, confers on tumor cells the genetic capacity to activate a prodrug locally, within the tumor, and is designed to increase antitumor activity while minimizing toxic side effects to critical host tissues.…”

Section: Mrp and Nqomentioning

confidence: 99%

Cancer Chemotherapy and Drug Metabolism

Riddick¹,

Lee²,

Ramji³

et al. 2005

Drug Metab Dispos

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Chemotherapy involving the use of cytotoxic antineoplastic agents remains an important strategy in the overall management of patients with malignant tumors. As with most therapeutic agents, drug-metabolizing enzymes and drug transporters play key roles in determining the pharmacokinetics and overall disposition of antineoplastic agents in the body. In addition, metabolism and transport can be important contributors to 1) the toxicity produced by antineoplastic agents in normal host tissues and 2) the delicate balance between drug sensitivity and resistance displayed by target tumor cells.Several features of antineoplastic drugs make the metabolism of these agents particularly significant. Many antineoplastics display steep dose-response curves and low therapeutic indices, and the toxicities that they produce can be severe and life-threatening. Since cancer chemotherapy often involves the use of multiple antineoplastic agents and supportive drugs in combination regimens, drug interactions represent a real clinical concern (Kivisto et al., 1995). Of particular importance are pharmacokinetic drug interactions that result in clinically significant alterations in host toxicity or therapeutic response. Pharmacokinetic drug interactions in cancer chemotherapy often go unrecognized because toxic reactions to these drugs are common and unpredictable, individual

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Section: Mrp and Nqomentioning

confidence: 99%

Cancer Chemotherapy and Drug Metabolism

Riddick¹,

Lee²,

Ramji³

et al. 2005

Drug Metab Dispos

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“…Gene-directed enzyme prodrug therapy is a two-step process which involves the delivery of a gene encoding an enzyme, followed by administration of a nontoxic prodrug, which is converted to a cytotoxin by the enzyme. Several GDEPT combinations have been proposed (Springer and Niculescu-Duvaz, 1996), the most studied being the Herpes Simplex virus thymidine kinase/gancyclovir system (van Dillen et al, 2002). This combination has entered clinical trials, and shown safety and some efficacy (Sandmair et al, 2000;Miles et al, 2001).…”

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confidence: 99%

Use of horseradish peroxidase for gene-directed enzyme prodrug therapy with paracetamol

2004

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Gene therapy is a potential method of treating cancer with a greater degree of targeting than conventional therapies. In addition, therapy can be directed towards cells within the tumour population that are traditionally resistant to current treatment schedules. Horseradish peroxidase (HRP) can oxidise paracetamol to N-acetyl-p-benzoquinoneimine via a one-electron pathway. Incubation of human cells expressing HRP with 0.5 -10 mM paracetamol reduced clonogenic survival, but had little effect on control cells. A small increase in apoptosis was seen and a decrease in the number of cells undergoing mitosis, consistent with reports in hepatocytes using higher paracetamol concentrations. The cytotoxicity was also seen under conditions of severe hypoxia (catalyst induced anoxia), indicating that the HRP/paracetamol combination may be suitable for hypoxia-targeted gene therapy.

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“…5-FU is a common moderately toxic anti-tumor drug for treating the digestive system cancers, liver cancer, breast cancer and other cancers in clinic, 5-FU has low toxicity to the normal cells, tissues and organs (Huber et al, 1994). 5-FU in the cancer cells is converted to 5-FUMP, the substance can combine with reduced tetrahydrofolic acid and thymidylate synthetase (TS) as a trimer to inactivate TS and prevent deoxyuridine acid from changing into deoxythymidine acid, which in turn inhibits DNA synthesis to achieve the goal of tumor inhibition (Springer, 1996;Arica et al, 2002;Springer et al, 2004;Kaliberova et al, 2008). In previous studies, some cytokines were expressed in recombinant NDV vectors, which are uncontrollable and may cause some unexpected side effects.…”

Section: Discussionmentioning

confidence: 99%