No Acceleration of UV-Induced Skin Carcinogenesis from Evenly Spread Dietary Intake of Cyclosporine in Contrast to Oral Bolus Dosages

Voskamp, Pieter; Bodmann, Carolien A.; Koehl, Gudrun E.; Tensen, Cornelis P.; Bavinck, Jan Nico Bouwes; Willemze, Rein; Geissler, Edward K.; Gruijl, Frank R. de

doi:10.1097/tp.0b013e3182a3dfa3

Cited by 4 publications

(5 citation statements)

References 17 publications

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“…In addition, the fact that immunosuppressed patients who switched from CsA to rapamycin dramatically reduced their risk of developing future SCCs (as long as they did not have multiple SCCs before conversion) is in alignment with the “intervention” model findings in Figure 2, which is supported by other treatment regimes [39, 41]. Additional studies in SKH-1 mice have found that dietary CsA exposure during UV protected against skin tumorigenesis, while post-UV dietary CsA had no effect and bolus treatments with the agent during UV increased tumor burden [46]. It is therefore possible that continuous versus intermittent dosing with rapamycin may also have differing effects on tumor outcomes.…”

Section: Discussionsupporting

confidence: 70%

Inhibition of Akt Enhances the Chemopreventive Effects of Topical Rapamycin in Mouse Skin

Dickinson

Janda

Criswell

et al. 2016

Cancer Prevention Research

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The PI3Kinase/Akt/mTOR pathway has important roles in cancer development for multiple tumor types, including UV-induced non-melanoma skin cancer. Immunosuppressed populations are at increased risk of aggressive cutaneous squamous cell carcinoma (SCC). Individuals who are treated with rapamycin, (sirolimus, a classical mTOR inhibitor) have significantly decreased rates of developing new cutaneous SCCs compared to those that receive traditional immunosuppression. However, systemic rapamycin use can lead to significant adverse events. Here we explored the use of topical rapamycin as a chemopreventive agent in the context of solar simulated light (SSL)-induced skin carcinogenesis. In SKH-1 mice, topical rapamycin treatment decreased tumor yields when applied after completion of 15 weeks of SSL exposure compared to controls. However, applying rapamycin during SSL exposure for 15 weeks, and continuing for 10 weeks after UV treatment, increased tumor yields. We also examined whether a combinatorial approach might result in more significant tumor suppression by rapamycin. We validated that rapamycin causes increased Akt (S473) phosphorylation in the epidermis after SSL, and show for the first time that this dysregulation can be inhibited in vivo by a selective PDK1/Akt inhibitor, PHT-427. Combining rapamycin with PHT-427 on tumor prone skin additively caused a significant reduction of tumor multiplicity compared to vehicle controls. Our findings indicate that patients taking rapamycin should avoid sun exposure, and that combining topical mTOR inhibitors and Akt inhibitors may be a viable chemoprevention option for individuals at high risk for cutaneous SCC.

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Section: Discussionsupporting

confidence: 70%

Inhibition of Akt Enhances the Chemopreventive Effects of Topical Rapamycin in Mouse Skin

Dickinson

Janda

Criswell

et al. 2016

Cancer Prevention Research

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“…The size of the immunosuppressed groups in this study was not designed to assess whether there is an effect of immunosuppression on tumor incidence and, therefore, we cannot draw any conclusions in this regard. Additionally, the administration regimen of CsA could have played a role in the lack of increased tumor formation, as it was recently shown in a UV-irradiated mouse model of skin cancer that CsA administered in a bolus rather than continuously is able to increase the number of tumors [56]. Nonetheless, we show that this vaccination strategy has credible potential in the difficult fight against skin lesions in immunosuppressed patients, especially those occurring in organ transplant recipients.…”

Section: Discussionmentioning

confidence: 57%

Protective Vaccination against Papillomavirus-Induced Skin Tumors under Immunocompetent and Immunosuppressive Conditions: A Preclinical Study Using a Natural Outbred Animal Model

et al. 2014

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Certain cutaneous human papillomaviruses (HPVs), which are ubiquitous and acquired early during childhood, can cause a variety of skin tumors and are likely involved in the development of non-melanoma skin cancer, especially in immunosuppressed patients. Hence, the burden of these clinical manifestations demands for a prophylactic approach. To evaluate whether protective efficacy of a vaccine is potentially translatable to patients, we used the rodent Mastomys coucha that is naturally infected with Mastomys natalensis papillomavirus (MnPV). This skin type papillomavirus induces not only benign skin tumours, such as papillomas and keratoacanthomas, but also squamous cell carcinomas, thereby allowing a straightforward read-out for successful vaccination in a small immunocompetent laboratory animal. Here, we examined the efficacy of a virus-like particle (VLP)-based vaccine on either previously or newly established infections. VLPs raise a strong and long-lasting neutralizing antibody response that confers protection even under systemic long-term cyclosporine A treatment. Remarkably, the vaccine completely prevents the appearance of benign as well as malignant skin tumors. Protection involves the maintenance of a low viral load in the skin by an antibody-dependent prevention of virus spread. Our results provide first evidence that VLPs elicit an effective immune response in the skin under immunocompetent and immunosuppressed conditions in an outbred animal model, irrespective of the infection status at the time of vaccination. These findings provide the basis for the clinical development of potent vaccination strategies against cutaneous HPV infections and HPV-induced tumors, especially in patients awaiting organ transplantation.

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“…Importantly, we were able to highlight the negative effects of using HCTZ in a population mainly treated with immunosuppressants belonging to the modern era, namely tacrolimus and mycophenolate mofetil. Indeed, as stated above, direct UV-induced carcinogenic effects are well documented with azathioprine, the maintenance therapy historically used in kidney transplantation, but such effects have not been established for cyclosporin, tacrolimus, and mycophenolate mofetil (20,34). With improvements in surveillance, this likely explains why the risk of squamous cell carcinoma in solid organ transplant recipients has drastically decreased in recent decades from 65 to 250 times (3) compared with the general population to 20 times (35,36).…”

Section: Discussionmentioning

confidence: 99%

Association between Use of Hydrochlorothiazide and Risk of Keratinocyte Cancers in Kidney Transplant Recipients

Letellier

Leborgne

Kerleau

et al. 2020

CJASN

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Background and objectivesKeratinocyte cancers, which primarily comprise squamous cell carcinomas and basal cell carcinomas, represent a major concern and potential risk for kidney transplant recipients. Hydrochlorothiazide, a diuretic widely used to treat hypertension, has been implicated in skin photosensitivity reaction. Recent studies conducted in the general population have found that hydrochlorothiazide use is associated with a higher risk of keratinocyte cancer, especially squamous cell carcinomas. High-risk groups, however, including transplant recipients were excluded from these. Our aim was to investigate whether hydrochlorothiazide use was associated with keratinocyte cancer in kidney transplant recipients on immunosuppressive therapy.Design, setting, participants, & measurementsIn a single-center cohort of kidney (n=2155), combined kidney-pancreas (n=282), and pancreas (n=59) transplant recipients from the Données Informatisées VAlidées Transplantation (DIVAT) database transplanted between 2000 and 2017 in Nantes, France, we evaluated the association between hydrochlorothiazide exposure and keratinocyte cancers. Multivariable cause-specific, time-varying Cox models were used to estimate the relationship between hydrochlorothiazide exposure and the hazard of squamous cell carcinoma and basal cell carcinoma, with hydrochlorothiazide designated as the time-dependent variable.ResultsAmong the participants, 279 of 2496 (11%) were exposed to hydrochlorothiazide after the transplantation. Cumulative incidence rates of keratinocyte cancer by 10 and 15 years were 7% and 9% for squamous cell carcinomas, respectively, and 8% and 11% for basal cell carcinomas, respectively. We found a relationship between exposure to hydrochlorothiazide and the risk of squamous cell carcinomas (hazard ratio, 2.04; 95% confidence interval, 1.27 to 3.28). In contrast, we found no association between hydrochlorothiazide exposure and basal cell carcinomas (hazard ratio, 0.63; 95% confidence interval, 0.35 to 1.15).ConclusionsIn a single-center cohort of kidney, combined kidney-pancreas, and pancreas transplant recipients, exposure to hydrochlorothiazide was associated with a two-fold higher risk of squamous cell carcinoma and no higher risk of basal cell carcinoma.

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No Acceleration of UV-Induced Skin Carcinogenesis from Evenly Spread Dietary Intake of Cyclosporine in Contrast to Oral Bolus Dosages

Cited by 4 publications

References 17 publications

Inhibition of Akt Enhances the Chemopreventive Effects of Topical Rapamycin in Mouse Skin

Inhibition of Akt Enhances the Chemopreventive Effects of Topical Rapamycin in Mouse Skin

Protective Vaccination against Papillomavirus-Induced Skin Tumors under Immunocompetent and Immunosuppressive Conditions: A Preclinical Study Using a Natural Outbred Animal Model

Association between Use of Hydrochlorothiazide and Risk of Keratinocyte Cancers in Kidney Transplant Recipients

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