Antiproliferative potential of zidovudine in human keratinocyte cultures

Bonnekoh, Bernd; Wevers, Andrea; Geisel, Jürgen; Rasokat, H.; Mahrle, G.

doi:10.1016/0190-9622(91)70228-t

Cited by 28 publications

(14 citation statements)

References 27 publications

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“…To verify whether AZT can be determined also in cell cultures, we chose to apply the SWV technique to human immortalized keratinocyte cell line HaCaT as an in vitro model for epidermal hyperproliferation [24,25]. We found that this HaCaT line shows high resistance towards AZT.…”

Section: The Detection Of Intracellular Aztmentioning

confidence: 99%

Determination of Azidothymidine – an Antiproliferative and Virostatic Drug by Square‐Wave Voltammetry

et al. 2004

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The 3'-azido-3'-deoxythymidine (AZT, Zidovudine) is an antiproliferative and virostatic drug widely used in human immunodeficiency virus type 1 (HIV-1) infection treatment. With respect to side effects of high doses and a short halflife of AZT, a fast and simple detection method for this agent could be helpful. The aim of our study was to determine AZT levels in natural samples (urine, serum, whole blood, and cell cultures, such as the HaCaT line of keratinocytes) without their mineralization and/or purification, by means of electrochemical methods using hanging mercury drop electrode (HMDE). On this electrode, AZT undergoes irreversible reduction at the peak potential near E p À 1.1 V (vs. Ag/AgCl/3 M KCl). Reduction AZT signals were measured by cyclic voltammetry (CV), differential pulse voltammetry (DPV), square-wave voltammetry (SWV), and constant current chronopotentiometric stripping analysis (CPSA). In phosphate buffer (pH 8) the SWV yielded the best AZT signal with the detection limit of 1 nM. The determination of AZT concentration in biological materials is affected by electroactive components, such as proteins and DNA. For monitoring the influence of these compounds, AZT reduction was performed in the presence of 10 mg/ mL calf thymus ssDNA and/or 100 mg/mL bovine serum albumin. In these cases, the detection limit increased to 0.25 mM. Also studied was the AZT concentration in keratinocyte cells (HaCaT line) during cell cultivation. It has been shown that the SWV may be considered as a useful tool for the determination of AZT concentration in cell cultures, and for monitoring AZT pharmacokinetics.

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Section: The Detection Of Intracellular Aztmentioning

confidence: 99%

Determination of Azidothymidine – an Antiproliferative and Virostatic Drug by Square‐Wave Voltammetry

et al. 2004

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“…As a first step dithranol (anthralin) and dimethylfumarate were studied as well-known topical and systemic antipsoriatics [20,21] in order to establish this experimental system including HaCaT keratinocytes [22], representing epidermal hyperproliferation typically observed in psoriatic involved skin [23].…”

Section: Introductionmentioning

confidence: 99%

Dithranol and Dimethylfumarate Suppress the Interferon-γ-Induced Up-Regulation of Cytokeratin 17 as a Putative Psoriasis Autoantigen in vitro

Bonnekoh

Böckelmann²,

Ambach³

et al. 2001

Skin Pharmacol Physiol

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In psoriasis an etiopathogenetic vicious circle has been hypothesized in which disease manifestation is triggered by skin-specific autoantigen structures. Autoreactive T cells are supposed to mediate inflammation and hyperproliferation in the epidermopapillary compartment, positively feeding back the expression and accessibility of decisive antigen structures. Recently an epitope within cytokeratin 17 (K17) has been described as such a putative psoriasis autoantigen, which is moreover known to be up-regulated under the influence of proinflammatory interferon-γ (IFN-γ), which is abundantly detected in psoriatic plaques. The present study proposes an in vitro model for this presumptive IFN-γ/K17 autoimmune loop, i.e. the incubation of hyperproliferative human HaCaT keratinocytes with 25 U IFN-γ/ml for 72 h. This treatment led to a significant up-regulation of K17 protein expression (≧300%) measured by flow immunocytometry as compared to the untreated control (100%, p ≤ 0.05). Preincubation with a subcytotoxic and antiproliferative dithranol concentration as low as 0.3 µM for 2 h prior to the IFN-γ exposure resulted in a K17 expression that was significantly lower than the IFN-γ-induced K17 expression reference level. The IFN-γ-induced K17 expression was also significantly lowered by coincubation with a subcytotoxic and nonantiproliferative concentration of 3 µM dimethylfumarate. The data indicate for dithranol and dimethylfumarate that a part of their antipsoriatic mode of action may be related to a direct down-regulation of putative psoriasis autoantigen structures.

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“…The antifolate methotrexate for example, is active as an antipsoriatic drug, but its deleterious side effects limit its usefulness [14]. Similarly, AZT, a nucleoside antimetabolite that acts as a chain terminator of DNA synthesis, has demonstrated activity in vivo against psoriasis [8]. Although other cellular sites of action are possible, these drugs inhibit keratinocyte proliferation, a key feature in psoriasis [15].…”

Section: Discussionmentioning

confidence: 99%

“…We have previously reported that methotrexate, 5-fluorouracil and several other related agents are irreversible inhibitors of keratinocyte proliferation and induce terminal differentiation [6,7]. 3)-Azidothymidine (AZT), a thymidine analog and anti-HIV agent, also inhibits proliferation of keratinocytes and acts as a chain terminator of DNA synthesis [8]; AZT has been reported to be an effective treatment for psoriasis [9]. We, therefore, examined the activity of L-(-)-OddC in proliferating human keratinocytes in vitro in comparison to AZT and related antimetabolites.…”

Section: Introductionmentioning

confidence: 99%

β-<i>L</i>-1,3-Dioxolane-Cytidine:A Novel Nucleoside ThatInhibits Proliferation andInduces Differentiation ofKeratinocytes in vitro

Schwartz

Haggerty

Cheng

1998

Skin Pharmacol Physiol

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β-L-1,3-Dioxolane-cytidine (L-(–)-OddC) is a novel L-nucleoside, and its antitumor activity is under investigation in clinical trials. To evaluate the potential of L-(–)-OddC for treating hyperproliferative diseases of the skin, we examined its activity in human keratinocytes in vitro. The dose of L-(–)-OddC that inhibited the rate of proliferation of keratinocytes by 50% was 50 nM. L-(–)-OddC was about as cytotoxic as 9-β-D-arabinofuranosylcytosine but was about 1,000 time more potent than 3′-azidothymidine. L-(–)-OddC caused irreversible growth arrest and induced differentiation of keratinocytes. L-(–)-OddC altered morphology, increased the cell size of keratinocytes and increased the expression of involucrin. These data suggest that L-(–)-OddC may have potential as a therapeutic agent against hyperproliferative skin diseases.

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Antiproliferative potential of zidovudine in human keratinocyte cultures

Cited by 28 publications

References 27 publications

Determination of Azidothymidine – an Antiproliferative and Virostatic Drug by Square‐Wave Voltammetry

Determination of Azidothymidine – an Antiproliferative and Virostatic Drug by Square‐Wave Voltammetry

Dithranol and Dimethylfumarate Suppress the Interferon-γ-Induced Up-Regulation of Cytokeratin 17 as a Putative Psoriasis Autoantigen in vitro

β-<i>L</i>-1,3-Dioxolane-Cytidine:A Novel Nucleoside ThatInhibits Proliferation andInduces Differentiation ofKeratinocytes in vitro

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