Gene therapy of cancer offers the possibility of a targeted treatment that destroys tumors and metastases, but not normal tissues. In gene-directed enzyme prodrug therapy (GDEPT), or suicide gene therapy, the gene encoding an enzyme is delivered to tumor cells, followed by administration of a prodrug, which is converted locally to a cytotoxin by the enzyme. The producer cells as well as surrounding bystanders are subsequently killed. Promising results have meant that suicide gene therapy has reached multicenter phase III clinical trials. This review will discuss the development, efficiency, mode of action and pharmacokinetics of seven GDEPT systems in vitro and in vivo. We will review the latest data of those systems in clinical trials (herpes simplex virus thymidine kinase/gancyclovir, bacterial cytosine deaminase/5-fluorocytosine, bacterial nitroreductase/CB1954 and cytochrome P450/cyclophosphamide), as well as the development of more recent and experimental systems which are not yet in clinical trials (P450 reductase/tirapazamine, carboxypeptidase/CMDA, horseradish peroxidase/indole-3-acetic acid or paracetamol and others).
Stimulation of the opioid receptor‐like1 (ORL‐1) receptor by nociceptin (NC) produces hyperalgesia and reverses the antinociceptive effects induced by opioids. Most studies concerning the central effects of NC were conducted using acute pain models. The role NC may play in chronic inflammation remains unelucidated. The present study was undertaken to assess the action of NC in the Freund's adjuvant‐induced monoarthritic rat model. The effects of drugs known to act as analgesics in this model were evaluated. The effects of NC, NCNH2, and the ORL‐1 ligand, [Phe1ψ(CH2‐NH)Gly2]NC(1‐13)NH2 ([F/G]NC(1‐13)NH2), were also studied alone or in association with morphine. NC (1–30 nmol, i.c.v.) was inactive, whilst NCNH2 (10 nmol, i.c.v.) exerted hyperalgesic effects (−4.5±0.9 vs −0.7±0.8 s of vehicle‐treated animals). [F/G]NC(1‐13)NH2 (0.01–10 nmol, i.c.v.) induced hyperalgesia in the arthritic paw (−3.3±0.6 vs −0.3±0.5 s of vehicle‐treated animals; 10 nmol). Both NC (0.01–10 nmol, i.c.v.) and [F/G]NC(1‐13)NH2 (0.01–1 nmol, i.c.v), 30 min after morphine (3 mg kg−1, s.c.) induced an immediate and short‐lived reversal of morphine effects (2.6±0.3 vs 10.4±1.0 and 1.2±1.5 vs 9.3±1.1 s of morphine alone, respectively), therefore displaying anti‐opioid activity. In the Freund's adjuvant‐induced rat model of arthritis, both NC and [F/G]NC(1‐13)NH2 act as anti‐opioid peptides. Furthermore, NCNH2 and [F/G]NC(1‐13)NH2 induce hyperalgesia when given alone. Further investigations and the identification of a centrally acting ORL‐1 antagonist are necessary to better understand the role of NC in pain mechanisms. British Journal of Pharmacology (1999) 128, 1252–1258; doi:
Gene-directed enzyme prodrug therapy is a form of targeted cancer therapy, in which an enzyme is used to convert a non-toxic prodrug to a cytotoxin within the tumor. Horseradish peroxidase (HRP) is able to convert the indole prodrugs indole-3-acetic acid (IAA) and the halogenated derivative 5-bromo-IAA (5Br-IAA) to toxic agents able to induce cell kill in vitro. This study characterized HRP-directed gene therapy in vivo. Human nasopharyngeal squamous cell carcinoma cells, FaDu, stably expressing HRP were grown as xenografts in SCID mice. Pharmacokinetic analysis of IAA and 5Br-IAA showed satisfactory drug profiles, and millimolar concentrations could be achieved in tumor tissue at non-toxic doses. HRP-expressing tumors showed a modest growth delay when treated with IAA compared with drug-vehicle controls. Treatment response could not be improved using different drug scheduling or drug vehicle, nor by combining HRP-directed gene therapy with fractionated radiotherapy.
Horseradish peroxidase has previously been shown to catalyze the conversion of indole-3-acetic acid (IAA) to a potent cytotoxin in a gene therapy setting. A three-dimensional spheroid model composed of a human head and neck carcinoma cell line, has been used to mimic the tumor microenvironment, such as regions of hypoxia. Exposure of intact spheroids to 0.05-5 mM concentrations of IAA and the halogenated indole, 5-bromoindole-3-acetic acid (5Br-IAA), resulted in decreased cell survival, and demonstrates that this combination is effective under tumor-simulated conditions. In addition, 5Br-IAA, displayed selectivity for spheroids with a large hypoxic fraction following short exposure times. Keywords: horseradish peroxidase; hypoxia; indoles; spheroids G ene-directed enzyme prodrug therapy (GDEPT) is a multistep strategy designed to specifically target tumor tissue and reduce normal tissue side effects. The gene coding for an enzyme is delivered to the tumor, followed by the administration of a nontoxic prodrug which can be converted to a cytotoxin by the enzyme, 1 thereby killing surrounding tumor cells.A variety of GDEPT combinations have been proposed, including the horseradish peroxidase/indole-3-acetic acid (HRP/IAA) combination. 2 HRP is a plant enzyme capable of converting the auxin IAA, and other indoles, to cytotoxins via a one-electron oxidation followed by subsequent nonenzymatic reactions. 3 An advantage of the HRP/IAA combination over several other enzyme/ prodrug combinations is that it is effective under hypoxia; a tumor-specific condition and an adverse prognostic factor in a variety of human tumors. 4 When put into a GDEPT setting, the combination is effective even under catalyst-induced anoxia, 5 and also when the expression of the enzyme is placed under the control of hypoxia response elements. 6 In this study, we used a multicellular spheroid model composed of human squamous cell carcinoma cells (FaDu), to mimic the microenvironmental conditions seen in human tumors. This allows evaluation of the HRP/IAA combination under tumor-simulated conditions prior to in vivo investigations. The more complex three-dimensional nature of spheroids compared with monolayers allows for a more heterogeneous cell population. Regions within the spheroid experience different environments, ranging from well oxygenated via hypoxic regions to the necrotic core, 7 accompanied by alterations in the nutrient composition. Oxygen has been shown to have a diffusion range through metabolizing cells of about 150 mm, which results in a diffusion limited, chronically hypoxic cell population in the spheroids.In this study, the efficacy of the HRP gene therapy system was analyzed in a multicellular spheroid system using a cell line with dysfunctional p53 activity. 8 Small and large spheroids with different hypoxic fractions were compared with monolayers. The parent compound IAA was also evaluated against a halogenated indole derivative, 5Br-IAA, which previously showed enhanced anoxic toxicity. 5 Materials and methods Cell cultur...
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