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Toxicity assessment in the discovery of new anticancer drugs
Abstracts / Toxicology Letters 172S (2007) S1–S240
further experiments should be conducted to confirm this data. ER␣ was not expressed neither in basal CBC and BM whereas ER was present. E2 was not able to modulate the expression of both the receptors on the basal cell population. Interestingly, in long-term human BM cultures, after 14 days of differentiation, ER␣ switched on and ER protein switched off. Further investigation is needed to understand the role of ER in haematopoiesis. doi:10.1016/j.toxlet.2007.05.566 Z10 Quantitative analysis of natural antioxidants pelargonidin and peonidin in fresh vegetables using an ODS-3 liquid chromatography column Nafiz Oncu Can, Goksel Altiokka Anadolu University, Eskisehir, Turkey As a subgroup of the polyphenols family, anthocyanins are known as one of the best natural antioxidant compounds that can be found in many of the vegetables. Anthocyanins, which act as colouring pigments in plants, have been shown to be strong antioxidants with potential health benefits. These properties make these compounds preferable as nutritional supplements and possible therapeutic agents against cancer and cardiovascular diseases. The aim of this study was to investigate the levels of two anthocyanins, pelargonidin and peonidin, in vegetables using an improved liquid chromatographic method. An ODS-3 reversed phase column (GL Sciences, Inertsil ODS-3, 3 m, 150 mm × 4.6 mm) was used to determine anthocyanin content of some commonly consumed vegetables. Obtaining excellent accuracy (recovery more than 99%) and precision (R.S.D.% <0.9), both compounds were separated with adequate resolution factor which was higher than 3. Pelargonidin and peonidin signals were found to be linear between the ranges of 78.1–390.7 and 83.2–415.7 ng/mL, giving limit of detection levels of 3.9 and 16.8 ng/mL for pelargonidin and peonidin, respectively. There is no intensive extraction steps were applied in order to keep the methodology as simple as possible. Towards this purpose, direct pressing was applied to the homogenized samples, and the juice extracted was injected to the system after filtration. As a result, it can be concluded that both anthocyanins exist at high levels especially in turnip and red cabbage,
S225
while there is no evidence was observed in carrot, red pepper and tomato. doi:10.1016/j.toxlet.2007.05.567 Z11 Toxicity assessment in the discovery of new anticancer drugs Marina Cattoni, Paolo Colombo, Marco Brughera Accelera Nerviano Medical Sciences s.r.l., Nerviano, Italy The shift from the development of non-specific cytotoxic anticancer agents to more specific molecular targeted drugs and the need to accelerate the initiation of clinical trials led to a re-evaluation of the toxicity assessment process, especially in the discovery and early development phases. The assessment of the toxicity profile of novel anticancer molecules begins earlier to identify key safety issues and address them at the stage of lead selection. Protein kinases are involved in the signaling pathways and molecular events inside the cells. Specific protein kinases have emerged as regulators of malignant behavior in cancer cells and represent promising targets for small-molecule inhibitors. Current strategies for new anticancer agents are increasingly focused on multi-targeting therapies against proteine kinases. While maximizing the efficacy, a multi-targeting approach can result in increased toxicity. Consequently, the safety of inhibiting target kinases has to be evaluated early in the project using molecular profiling tools to understand its relevance in healthy tissues and across species. In addition, early endpoints of toxicity, such as monitoring of in vivo parameters and the inclusion of targeted pathology examination, could be incorporated in efficacy models to assess a preliminary safety margin. Preliminary repeated-dose toxicology studies are performed in rodents to identify main target organ toxicities and schedule dependency. Furthermore, customized in vitro models with individual specific endpoints could be developed. Once a possible candidate has been identified, non-rodent toxicity studies are performed to evaluate species specificity or sensitivity. Case examples of this approach are presented and discussed. doi:10.1016/j.toxlet.2007.05.568
further experiments should be conducted to confirm this data. ER␣ was not expressed neither in basal CBC and BM whereas ER was present. E2 was not able to modulate the expression of both the receptors on the basal cell population. Interestingly, in long-term human BM cultures, after 14 days of differentiation, ER␣ switched on and ER protein switched off. Further investigation is needed to understand the role of ER in haematopoiesis. doi:10.1016/j.toxlet.2007.05.566 Z10 Quantitative analysis of natural antioxidants pelargonidin and peonidin in fresh vegetables using an ODS-3 liquid chromatography column Nafiz Oncu Can, Goksel Altiokka Anadolu University, Eskisehir, Turkey As a subgroup of the polyphenols family, anthocyanins are known as one of the best natural antioxidant compounds that can be found in many of the vegetables. Anthocyanins, which act as colouring pigments in plants, have been shown to be strong antioxidants with potential health benefits. These properties make these compounds preferable as nutritional supplements and possible therapeutic agents against cancer and cardiovascular diseases. The aim of this study was to investigate the levels of two anthocyanins, pelargonidin and peonidin, in vegetables using an improved liquid chromatographic method. An ODS-3 reversed phase column (GL Sciences, Inertsil ODS-3, 3 m, 150 mm × 4.6 mm) was used to determine anthocyanin content of some commonly consumed vegetables. Obtaining excellent accuracy (recovery more than 99%) and precision (R.S.D.% <0.9), both compounds were separated with adequate resolution factor which was higher than 3. Pelargonidin and peonidin signals were found to be linear between the ranges of 78.1–390.7 and 83.2–415.7 ng/mL, giving limit of detection levels of 3.9 and 16.8 ng/mL for pelargonidin and peonidin, respectively. There is no intensive extraction steps were applied in order to keep the methodology as simple as possible. Towards this purpose, direct pressing was applied to the homogenized samples, and the juice extracted was injected to the system after filtration. As a result, it can be concluded that both anthocyanins exist at high levels especially in turnip and red cabbage,
S225
while there is no evidence was observed in carrot, red pepper and tomato. doi:10.1016/j.toxlet.2007.05.567 Z11 Toxicity assessment in the discovery of new anticancer drugs Marina Cattoni, Paolo Colombo, Marco Brughera Accelera Nerviano Medical Sciences s.r.l., Nerviano, Italy The shift from the development of non-specific cytotoxic anticancer agents to more specific molecular targeted drugs and the need to accelerate the initiation of clinical trials led to a re-evaluation of the toxicity assessment process, especially in the discovery and early development phases. The assessment of the toxicity profile of novel anticancer molecules begins earlier to identify key safety issues and address them at the stage of lead selection. Protein kinases are involved in the signaling pathways and molecular events inside the cells. Specific protein kinases have emerged as regulators of malignant behavior in cancer cells and represent promising targets for small-molecule inhibitors. Current strategies for new anticancer agents are increasingly focused on multi-targeting therapies against proteine kinases. While maximizing the efficacy, a multi-targeting approach can result in increased toxicity. Consequently, the safety of inhibiting target kinases has to be evaluated early in the project using molecular profiling tools to understand its relevance in healthy tissues and across species. In addition, early endpoints of toxicity, such as monitoring of in vivo parameters and the inclusion of targeted pathology examination, could be incorporated in efficacy models to assess a preliminary safety margin. Preliminary repeated-dose toxicology studies are performed in rodents to identify main target organ toxicities and schedule dependency. Furthermore, customized in vitro models with individual specific endpoints could be developed. Once a possible candidate has been identified, non-rodent toxicity studies are performed to evaluate species specificity or sensitivity. Case examples of this approach are presented and discussed. doi:10.1016/j.toxlet.2007.05.568