Glutathione transferases (GSTs) are often overexpressed in tumors and frequently correlated to bad prognosis and resistance against a number of different anticancer drugs. To selectively target these cells and to overcome this resistance we previously have developed prodrugs that are derivatives of existing anticancer drugs (e.g., doxorubicin) incorporating a sulfonamide moiety. When cleaved by GSTs, the prodrug releases the cytostatic moiety predominantly in GST overexpressing cells, thus sparing normal cells with moderate enzyme levels. By modifying the sulfonamide it is possible to control the rate of drug release and specifically target different GSTs. Here we show that the newly synthesized compounds, 4-acetyl-2-nitro-benzenesulfonyl etoposide (ANS–etoposide) and 4-acetyl-2-nitro-benzenesulfonyl doxorubicin (ANS–DOX), function as prodrugs for GSTA1 and MGST1 overexpressing cell lines. ANS–DOX, in particular, showed a desirable cytotoxic profile by inducing toxicity and DNA damage in a GST-dependent manner compared to control cells. Its moderate conversion of 500 nmol/min/mg, as catalyzed by GSTA1, seems hereby essential since the more reactive 2,4-dinitrobenzenesulfonyl doxorubicin (DNS–DOX) (14000 nmol/min/mg) did not display a preference for GSTA1 overexpressing cells. DNS–DOX, however, effectively killed GSTP1 (20 nmol/min/mg) and MGST1 (450 nmol/min/mg) overexpressing cells as did the less reactive 4-mononitrobenzenesulfonyl doxorubicin (MNS–DOX) in a MGST1-dependent manner (1.5 nmol/min/mg) as shown previously. Furthermore, we show that the mechanism of these prodrugs involves a reduction in GSH levels as well as inhibition of the redox regulatory enzyme thioredoxin reductase 1 (TrxR1) by virtue of their electrophilic sulfonamide moiety. TrxR1 is upregulated in many tumors and associated with resistance to chemotherapy and poor patient prognosis. Additionally, the prodrugs potentially acted as a general shuttle system for DOX, by overcoming resistance mechanisms in cells. Here we propose that GST-dependent prodrugs require a conversion rate “window” in order to selectively target GST overexpressing cells, while limiting their effects on normal cells. Prodrugs are furthermore a suitable system to specifically target GSTs and to overcome various drug resistance mechanisms that apply to the parental drug.

The present study aimed to meta-analyze and evaluate the certainty of evidence for resin infiltration of proximal carious lesions in primary and permanent teeth. While resin infiltration has been shown efficacious for caries management, the certainty of evidence remains unclear. The protocol was registered with PROSPERO (CRD42018080895), and PRISMA guidelines have been followed. The databases PubMed, Embase, and Cochrane CENTRAL were systematically screened, complemented by hand searches and cross-referencing. Eleven relevant articles were identified and included, i.e., randomized controlled trials (RCTs) comparing the progression of resin infiltrated proximal caries lesions (combined with non-invasive measures) in primary or permanent teeth with non-invasive measures. Random-effects meta-analyses and trial sequential analyses (TSA) were performed for per-protocol (PP), intention-to-treat (ITT), and best/worst case (BC/WC) scenarios. Six included trials assessed lesions in permanent teeth and five trails assessed lesions in primary teeth. The trials had a high or unclear risk of bias. Risk of caries progression was significantly reduced for infiltrated lesions in the PP, ITT, and BC scenarios in both permanent teeth and primary teeth, but not in the WC scenario. According to the TSA, firm evidence was reached for all of the scenarios except the WC. In conclusion, there is firm evidence for resin infiltration arresting proximal caries lesions in permanent and primary teeth.

The aim of this systematic review and meta-analysis was to evaluate the masking success of bleaching and/or resin infiltration treatment of fluorotic lesions in anterior teeth of adults and adolescents. PubMed, Cochrane Library, and Embase were systematically searched from the beginning of documentation to December 31, 2023. A tooth was considered masked when the color difference (ΔE CIE76) between fluorotic areas and the surrounding sound enamel was ≤3.7 and unmasked if ΔE > 3.7. Secondary outcomes were mean ΔE values between fluorotic and sound enamel reported for a treatment group at baseline and after any intervention as well as patient satisfaction. Of 1575 search results 4 publications met the inclusion criteria, comprising 230 treated anterior teeth with fluorosis in 47 patients. Meta-analyses were performed comparing the result after treatment (bleaching, resin infiltration, or bleaching followed by resin infiltration) to baseline. Bleaching and resin infiltration were suitable intervention strategies to improve the esthetics of fluorosis affected anterior teeth, with a combination of both treatment approaches being particularly effective in reducing the color difference between fluorotic defects and the surrounding sound enamel below the acceptability thresholds of 3.7 (success rate [95 %CI]: 0.75 [0.44, 1.06]). Patient satisfaction increased after treatments, indicating a beneficial impact on their mental health. The overall bias of the included studies was 2.5 (ROBINS-I analysis tool). There is evidence that resin infiltration with preceding bleaching therapy is more effective in masking fluorotic lesions in anterior teeth than bleaching alone. The combination therapy also showed a tendency towards higher success rates compared to infiltration alone. However, this difference was statistically not significant, and more studies are needed to further assess the efficacy of specific treatments and their combinations as well as the certainty in the evidence. The methodologic heterogeneity of study designs regarding estimation of color difference before and after treatment and bleaching protocols calls for unification in future studies. Results of this systematic review and meta-analysis revealed the combination of bleaching followed by resin infiltration as efficacious approach for masking fluorotic lesions in young adults. While resin infiltration alone improves the aesthetic appearance of fluorotic lesions, dentists should consider a combined bleaching-infiltration regimen to achieve more favorable clinical outcome for their patients.

Success of resin infiltration for the masking of MIH-lesions remains difficult to predict, prompting suggestions to adjust the treatment protocol. This exploratory in vivo study aims to evaluate whether monitoring the resin infiltration process using transmitted light, compared to ambient light, enables a better estimation of when the infiltration process is completed, and to assess how the treatment success, i.e. masking effect and infiltration proportion, is influenced accordingly. 15 patients with 19 MIH-lesions, diagnosed according to EAPD diagnostic criteria, were enrolled. MIH-lesions were randomly assigned to two treatment groups. In one group resin infiltration progression was monitored under transmitted light, whereas in the second group ambient light was used, representing the standard procedure. Pictures were taken before infiltration and when progression became evident until infiltration was judged to be completed. Infiltration proportion and color difference between the opacity and surrounding sound enamel were calculated and analyzed using the independent-sample t-test with a level of significance of p < 0.05. Compared to the ambient light group, the transmitted light group showed a significantly higher infiltration time (17.7 ± 8.2 min vs. 9.3 ± 1.6 min); a significantly higher mean infiltration proportion (97.6 ± 2.8% vs. 83.9 ± 9.7%) and a significantly better masking effect (i.e. lower mean color difference (∆E) between effected and sound enamel: 4.5 ± 2.4 vs. 7.5 ± 3.3). Transillumination-guided resin infiltration required prolonged infiltration time but led to an increased infiltration proportion and improved masking effects. Transillumination guided resin infiltration enables a more accurate judgement as to when the infiltration process has been completed, which leads, through extension of the infiltration time, to a significantly higher mean infiltration proportion and provides favorable esthetic outcomes.

To compile the available evidence on the effectiveness of resin infiltration in masking demarcated opacities in permanent incisors with MIH and whether modifications to the treatment protocol impact the outcome. This review followed PRISMA2020 and was registered in PROSPERO (CRD42023414048). Searches were performed in MedLine, LILACS, BBO, Cochrane, Web of Science, Scopus, Embase, OpenGrey, and Google Scholar, by two independent reviewers. JBI and RoB2 were used to evaluate risk of bias. R software was used to perform meta-analyses. Eight uncontrolled, two non-randomized, and two RCTs evaluated 369 teeth in 6-31year-old participants. Six studies followed the standard resin infiltration protocol, while the others reported modifications. The meta-analysis estimated an overall proportion of total masking of 37 % (CI: 18-55). Modified protocols tended to achieve higher success rates (40 %; CI: 9-72) compared to standard protocols (30 %; CI: 17-44), though this difference was not statistically significant. The overall reduction in ΔE was 3.08 (CI: 0.74-5.42), with 1.54 (CI: 0.68-2.40) for standard protocols and 3.84 (CI: 0.80-6.89) for modified ones. Seven studies had moderate risk of bias, and three had high risk. The certainty of evidence was low due to heterogeneity (I² > 80 %) and imprecision concerns. Resin infiltration is effective in reducing the color difference between MIH opacity and normal enamel. The achievement of total masking was not significantly different between the standard and modified protocols. Heterogeneity and lack of controlled studies limit the certainty of evidence. This review reinforces the effectiveness of resin infiltration in reducing the color difference between MIH opacity and normal enamel. Modifications in the protocol improved the infiltration but were not enough to be significantly superior. This review contributes to the understanding of peculiarities related to the microinvasive esthetic treatment of MIH.