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Context: Many tyrosine kinase inhibitors (TKIs) have been studied in patients with thyroid carcinoma (TC). However, the effect and toxicity of various TKIs in differentiated TC (DTC) and medullary TC (MTC) patients have not been directly compared. The aim of the present systematic review and meta-analysis was to systematically summarize response and toxicity of TKIs in TC patients. Methods: All major databases were systematically searched for publications on TKIs in TC. Primary endpoint was objective response; secondary endpoints were clinical benefit, percentage TKI dose reduction/discontinuation, hand-foot syndrome, diarrhea, and nausea/vomiting. Meta-analysis was performed using an exact likelihood approach and a logistic regression. Pooled percentages and 95% CIs were reported. Results: In total, 22 publications were included. For DTC patients, gefitinib induced no objective responses. Pooled percentage was highest for pazopanib, 49 (95% CI 33-64)%, and was 17 (95% CI 12-24)% for sorafenib. For MTC, gefitinib and imatinib induced no objective responses, whereas sunitinib induced objective response in 43 (95% CI 14-77)%. For vandetanib and cabozantinib, these numbers were 40 (95% CI 34-46)% and 27 (95% CI 22-32)% respectively. Clinical benefit was found in 53 (95% CI 48-59)% of DTC patients on sorafenib, and in 84 (95% CI 79-88)% and 55 (95% CI 49-61)% of MTC patients on vandetanib and cabozantinib respectively. All TKIs were associated with considerable toxicity. Conclusion: The currently studied TKIs show a modest response, while side effects are not negligible. Therefore, we suggest to solely consider TKIs in TC patients with rapid progressive disease, for whom the benefits of treatment outweigh toxicity.

Several recent studies have shown cysteine derivatives can protect against negative effects of UV exposure. In this study, an attempt was made to correlate cellular bioavailability and metabolism of cysteine derivatives with protection against UV-induced reactive intermediates. Human keratinocytes were treated with cysteine, N-acetylcysteine (NAC), cysteine-ethylester (CYSET) and N-acetylcysteine-ethylester. The uptake of the compounds and their metabolism to cysteine and eventually to glutathione (GSH) was measured. Large differences in uptake were observed, with CYSET resulting in the highest and NAC in the lowest intracellular thiol levels. The increase in intracellular GSH was similar for all derivatives with a maximum of 23-54% over the control level. Protective efficacy of the derivatives was measured as the inhibition of binding of UV-induced reactive intermediates from 8-methoxypsoralen. There was only a small difference between the compounds, with maximum protection of 25-31%. No relation was found between total intracellular thiol and protection. However, for NAC, there was a linear relation between GSH level and protective efficacy (r = 0.94). Even though this was not clear for the other derivatives (r = 0.55 for CYS; r = 0.60 for CYSET; r = 0.70 for NACET), it indicates that GSH synthesis is an important factor. This was confirmed by experiments using cells with irreversibly inhibited GSH synthesis. Even though the total intracellular thiol level was comparable to uninhibited cells, protection was decreased. We conclude that the intracellular GSH increase is the most important factor in photoprotection by cysteine derivatives.

Irradiation of the skin with ultraviolet-B (UVB) radiation causes a local and systemic suppression of T-cell-mediated immune responses. Recently, N-acetylcysteine (NAC) was found to protect against UVB-induced immunosuppression and several other types of UV damage. The protective effects appeared to be based on the ability of NAC to increase glutathione (GSH) levels by promoting GSH synthesis. In this study, it was investigated whether topical application of NAC was still effective against UVB-induced suppression of contact hypersensitivity if GSH synthesis was blocked. Mice were pretreated with buthionine sulfoximine (BSO), an inhibitor of GSH synthesis, which succeeded in blocking the increase in epidermal GSH after topical application of NAC. Whereas the non-BSO-treated animals showed an increase to around 155% of the control GSH level for all NAC doses tested, only a slight (nonsignificant) increase in epidermal GSH was observed in the BSO-treated animals. Surprisingly, the protective efficacy of NAC against UVB-induced immunosuppression was not affected by the BSO pretreatment. No significant difference between the protective efficacy of NAC in the two groups was observed. Apparently, the antioxidant effect of NAC itself was sufficient to provide protection against UVB-immunosuppression, independent of GSH synthesis.

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