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BackgroundActinic keratoses (AK) are pre-malignant cutaneous lesions caused by prolonged exposure to ultraviolet radiation. As AKs lesions are generally accepted to be the initial lesions in a disease continuum that progresses to squamous cell carcinoma (SCC), AK lesions have to be treated. They are also the second most common reason for visits to the dermatologist. Several treatments are available but their efficacy still needs to be improved. The UV-B-induced KA lesion mouse model is used in preclinical studies to assess the efficacy of novel molecules, even though it is often more representative of advanced AK or SCC.ObjectivesHere we report on a translational study, comparing the various stages of AK development in humans and in the UV-B irradiated mouse model, as well as the optimization of photograph acquisition of AK lesions on mouse skin.MethodsHuman and mouse skin lesions were analysed by histology and immunohistochemistry. Mouse lesions were also assessed using a digital dermatoscope.ResultsAn histological and phenotypic analysis, including p53, Ki67 and CD3 expression detection, performed on human and mouse AK lesions, shows that overall AK modelling in mice is relevant in the clinical situation. Some differences are observed, such as disorganization of keratinocytes of the basal layer and a number of atypical nuclei which are more numerous in human AK, whereas much more pronounced acanthosis is observed in skin lesion in mice. Thanks to this translational study, we are able to select appropriate experimental conditions for establishing either early or advanced stage AK or an SCC model. Furthermore, we optimized photograph acquisition of AK lesions on mouse skin by using a digital dermatoscope which is also used in clinics and allows reproducible photograph acquisition for further reliable assessment of mouse lesions. Use of this camera is illustrated through a pharmacological study assessing the activity of CARAC®.ConclusionThese data demonstrate that this mouse model of UV-B-induced skin lesions is predictive for the identification of novel therapeutic treatments for both early and advanced stages of the disease.

The aim of the present study was to determine whether donitriptan and sumatriptan decreased jugular venous oxygen saturation and increased carbon dioxide partial pressure in venous blood. However, previous studies conducted with these compounds cannot discriminate whether the decrease of venous oxygen saturation is dependent of cranial vasoconstrictor. In the present study, vehicle (n ϭ 10), donitriptan (2.5, 10, and 40 g/kg; n ϭ 8) or sumatriptan (630 g/kg; n ϭ 8) were infused into the carotid artery in the anesthetized rat. Regional blood flows were evaluated in the presence of donitriptan (10 g/kg; n ϭ 6) or vehicle (n ϭ 6). Jugular venous oxygen saturation was significantly decreased by donitriptan (from 10 g/kg) with maximal changes of Ϫ32.9 Ϯ 8.0%. Jugular carbon dioxide partial pressure was increased by donitriptan, reaching maximal changes of 17.7 Ϯ 4.6% (P Ͻ 0.05 versus vehicle). Similarly, sumatriptan significantly decreased venous oxygen saturation and increased jugular carbon dioxide partial pressure. These changes induced by donitriptan are abolished by the 5-hydroxytryptamine (5-HT) 1B/1D receptor antagonist. In addition, donitriptan was devoid of significant effects on systemic arterial pressure, heart rate, or regional blood flows, including systemic arterial-jugular venous anastomotic, systemic, or cranial. The results demonstrate that donitriptan increases cerebral oxygen consumption by 5-HT 1B/1D receptor activation in the absence of cranial vasoconstriction.The current mechanism(s) of action of 5-HT 1B/1D receptor agonists (triptans) in the acute relief of migraine headache is considered to comprise cranial vasoconstriction (Humphrey and Feniuk, 1991), peripheral neuronal inhibition (Moskowitz, 1992), and inhibition of transmission through secondorder neurons of the trigeminocervical complex (Hoskin et al., 1996), leading to inhibition of the effects of activated nociceptive terminal afferents (Goadsby, 2000). Donitriptan, which has been evaluated for efficacy in the acute relief of migraine headache in phase II clinical trials (Dukat, 2001), and other triptans (Létienne et al., 2003a) augmented cerebral oxygen utilization and tissue metabolism. This additional mechanism of action may also be relevant to the acute headache-relieving effects of triptans as a whole. However, our previous studies in the anesthetized pig (Létienne et al., 2003a,b) showed that the triptans increased arteriovenous oxygen saturation difference and carbon dioxide partial pressure in venous blood draining the head but also produced concomitant carotid vasoconstriction. Consequently, it was not possible to determine whether these events occurred independently.The aim of the present investigation was therefore to determine whether donitriptan and sumatriptan produced similar effects on jugular venous blood gas parameters in a model in which triptans are considered not to produce cranial vasoconstriction. Thus, the study was performed in anestheArticle, publication date, and citation information can be found at

Chemotherapy remains mainly used for the treatment of Acute Myelogenous Leukemia (AML). However, in the past 3 decades limited progress has been achieved in improving the long-term disease-free survival. Therefore the development of more effective drugs for AML represents a high level of priority. F14512 combines an epipodophyllotoxin core targeting topoisomerase II with a spermine moiety introduced as a cell delivery vector. In fact the polyamine moiety facilitates F14512 selective uptake by tumor cells via the polyamine transport system, a machinery frequently overactivated in cancer cells. In this study, we report the in vivo antileukemic activity of F14512 against human AML models, established from patient samples. AML cells, collected from 3 different patients, were established onto NSG mice (LAM-2, LAM-7 and LAM-18). These 3 AML samples exhibited a normal karyotype, with FLT3-ITD, NPM1 and DNMTA3 mutations which proved stable over serial transplantations in vivo. After multiple i.v. administrations of F14512, 3 times a week for 3 weeks, an extensive reduction of AML cell number (98–99%) was observed in LAM-2 and LAM-7 - bearing mice. This antileukemic activity was recorded on the basis of flow cytometry, q-PCR and histology assessments. The effects of F14512 on LAM-18 bearing mice were marginal with an inhibition of AML cell growth of 42%. We also show in vitro and in vivo synergistic effects of F14512 in combination with AraC, one of the frontline chemotherapeutic agents for AML. These results were obtained using the HL-60 cell line. The activity of F14512 in combination with AraC will be further investigated in patient AML models. Collectively, these results demonstrate that F14512 exhibits a marked in vivo antileukemic activity, supporting its clinical development. Phase I clinical trials in onco-hematology are on going with this novel promising drug candidate. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A214.

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