No description available.

<p>Background and objectives: Apoptosis is a process in which a cell programmes its own death. It is a highly organized physiological mechanism in which injured or damaged cells are destroyed. Apart from physiological stimuli however, exogenous factors can induce apoptosis. Many anti-cancer drugs work by activating apoptosis in cancer cells. Natural substances have been found to have the ability to induce apoptosis in various tumour cells and these substances have been used as templates for the construction of&nbsp / novel lead compounds in anticancer treatment. On the other hand, alkylating agents such as cisplatin, cis- [PtCl2 (NH3) 2] have been widely used as antineoplastic agents for a&nbsp / wide variety of cancers including testicular, ovarian, neck and head cancers, amongst others. However, the use of cisplatin as an anticancer agent is limited due to toxicity and resistance problems. The aim of this present study was to screen the leaves of Rhus laevigata, a South African indigenous plant, for the presence of pro-apoptotic and&nbsp / anti-proliferative natural compounds and also to screen newly synthesised palladium based complexes (15 and 57) and a platinum based complex (58) for their antineoplastic&nbsp / activities tested against a panel of cell lines. Results. The results showed that crude methanol extracts from Rhus laevigata as well as the newly synthesised palladium based complexes (15 and 57) and a platinum based complex (58) induced apoptosis in the cell lines tested, as demonstrated by the externalization of phosphatidylserine, mitochondrial membrane permeabilization,caspase-3 activation, and DNA fragmentation. Caski (cervical cancer) and H157 (non small cell lung carcinoma) cell lines treated with the methanol extract from Rhus laevigata however, were more resistant to apoptosis induction. Among the metallocomplexes, complexes 15 and 57, palladium based complexes, were the most active. Conclusion: The methanol extract from the leaves of Rhus laevigata contain pro-apoptotic and antiproliferative natural compound(s), which need to be characterised and elucidated as they could provide the much-needed lead compounds in the fight against cancer. On the other hand the newly synthesized palladium complexes also need further evaluation to&nbsp / see if they can be used as anticancer agents that can overcome the problems associated with cisplatin.</p>

Είναι ευρέως γνωστό από παλιά ότι οι μουστάρδες του αζώτου όταν είναι συνδεδεμένες μέσω ενός εστερικού δεσμού με ένα στεροειδές μόριο ή με ένα τροποποιημένο στεροειδές, τότε εμφανίζουν μικρότερη τοξικότητα και καλύτερη αντινεοπλασματική δράση. Προκειμένου να επιβεβαιώσουμε το ρόλο του στεροειδικού μορίου στην έκφραση της αντιλευχαιμικής ενεργότητας, επανασυνθέσαμε 16 ανάλογα της μουστάρδας 4-Μe-CABA και τα εξετάσαμε στη λευχαιμία Ρ388 in vivo και σε φυσιολογικά ανθρώπινα λεμφοκύτταρα in vitro. H πλειοψηφεία των εξεταζόμενων ενώσεων εμφάνισε χαμηλή τοξικότητα-χαμηλότερη τοξικότητα από αυτήν της μουστάρδας- ενώ η αντιλευχαιμική δράση αυξήθηκε σημαντικά. Όσον αφορά στις τροποποιήσεις αποδείχτηκε για μια ακόμη φορά ότι η ύπαρξη της ΝΗ-CΟ ομάδας ως εξωκυκλικό αμίδιο συνεισεφέρει σημαντικά στην δράση του μορίου μόνο όμως όταν βρίσκεται σε β-διαμόρφωση. Η μετατροπή του Β αλλά και του D στεροειδικού σκελετού σε λακταμικό ενίσχυσε την αντιλευχαιμική δράση των μορίων. Επίσης τα 7-οξειδωμένα παράγωγα αποδείχτηκαν καλύτερα από τα μη οξειδωμένα ανάλογα. Τα ευρήματα μας υποστηρίζουν ότι το στεροειδικό κομμάτι αυτών των ενώσεων δεν είναι μία απλή βιολογική πλατφόρμα όπως εικαζόταν για χρόνια. / It is commonly known that nitrogen mustards when conjugated with steroids or modified steroids via esteric bond show low toxicity and better antileukemic activity. In order to confirm the role of the steroidal moiety on the expression of anti-leukemic activity we re-synthesized 15 derivatives of the 4-Μe-CABA mustard and tested them on leukaemia P388 in vivo and in normal human lymphocytes in vitro.The majority of the tested compounds showed low toxicity while the measured antileukemic potency was significantly increased.As far as the modifications that were tested, once more it was proved that the existence of the ΝΗ-CΟ moiety when out of the ring as an amidic group contributes significantly to the activity of the molecule only if it is at axial conformation. The lactamization of the B-steroidal ring as well as the lactamization of the D-steroidal ring rendered the molecule more potent. Furthermore the 7-oxidized derivatives proved better than the non-7-oxidized derivatives. Our findings support the notion that the steroidal part of these molecules is not just a simple biological platform as has been speculated for years.

<p>Background and objectives: Apoptosis is a process in which a cell programmes its own death. It is a highly organized physiological mechanism in which injured or damaged cells are destroyed. Apart from physiological stimuli however, exogenous factors can induce apoptosis. Many anti-cancer drugs work by activating apoptosis in cancer cells. Natural substances have been found to have the ability to induce apoptosis in various tumour cells and these substances have been used as templates for the construction of&nbsp / novel lead compounds in anticancer treatment. On the other hand, alkylating agents such as cisplatin, cis- [PtCl2 (NH3) 2] have been widely used as antineoplastic agents for a&nbsp / wide variety of cancers including testicular, ovarian, neck and head cancers, amongst others. However, the use of cisplatin as an anticancer agent is limited due to toxicity and resistance problems. The aim of this present study was to screen the leaves of Rhus laevigata, a South African indigenous plant, for the presence of pro-apoptotic and&nbsp / anti-proliferative natural compounds and also to screen newly synthesised palladium based complexes (15 and 57) and a platinum based complex (58) for their antineoplastic&nbsp / activities tested against a panel of cell lines. Results. The results showed that crude methanol extracts from Rhus laevigata as well as the newly synthesised palladium based complexes (15 and 57) and a platinum based complex (58) induced apoptosis in the cell lines tested, as demonstrated by the externalization of phosphatidylserine, mitochondrial membrane permeabilization,caspase-3 activation, and DNA fragmentation. Caski (cervical cancer) and H157 (non small cell lung carcinoma) cell lines treated with the methanol extract from Rhus laevigata however, were more resistant to apoptosis induction. Among the metallocomplexes, complexes 15 and 57, palladium based complexes, were the most active. Conclusion: The methanol extract from the leaves of Rhus laevigata contain pro-apoptotic and antiproliferative natural compound(s), which need to be characterised and elucidated as they could provide the much-needed lead compounds in the fight against cancer. On the other hand the newly synthesized palladium complexes also need further evaluation to&nbsp / see if they can be used as anticancer agents that can overcome the problems associated with cisplatin.</p>

Thesis (Ph. D.)--West Virginia University, 2008. / Title from document title page. Document formatted into pages; contains xi, 109 p. : ill. (some col.). Includes abstract. Includes bibliographical references (p. 92-109).

Magister Scientiae - MSc / Apoptosis is a process in which a cell programmes its own death. It is a highly organized physiological mechanism in which injured or damaged cells are destroyed. Apart from physiological stimuli however, exogenous factors can induce apoptosis. Many anti-cancer drugs work by activating apoptosis in cancer cells. Natural substances have been found to have the ability to induce apoptosis in various tumour cells and these substances have been used as templates for the construction of novel lead compounds in anticancer treatment. On the other hand, alkylating agents such as cisplatin, cis- [PtCl2 (NH3) 2] have been widely used as antineoplastic agents for a wide variety of cancers including testicular, ovarian, neck and head cancers, amongst others. However, the use of cisplatin as an anticancer agent is limited due to toxicity and resistance problems. The aim of this present study was to screen the leaves of Rhus laevigata, a South African indigenous plant, for the presence of pro-apoptotic and anti-proliferative natural compounds and also to screen newly synthesised palladium based complexes (15 and 57) and a platinum based complex (58) for their antineoplastic activities tested against a panel of cell lines. Results. The results showed that crude methanol extracts from Rhus laevigata as well as the newly synthesised palladium based complexes (15 and 57) and a platinum based complex (58) induced apoptosis in the cell lines tested, as demonstrated by the externalization of phosphatidylserine, mitochondrial membrane permeabilization, caspase-3 activation, and DNA fragmentation. Caski (cervical cancer) and H157 (non small cell lung carcinoma) cell lines treated with the methanol extract from Rhus laevigata however, were more resistant to apoptosis induction. Among the metallocomplexes, complexes 15 and 57, palladium based complexes, were the most active. Conclusion The methanol extract from the leaves of Rhus laevigata contain pro-apoptotic and antiproliferative natural compound(s), which need to be characterised and elucidated as they could provide the much-needed lead compounds in the fight against cancer. On the other hand the newly synthesized palladium complexes also need further evaluation to see if they can be used as anticancer agents that can overcome the problems associated with cisplatin.

Magister Scientiae - MSc / Background and objectives: Apoptosis is a process in which a cell programmes its own death. It is a highly organized physiological mechanism in which injured or damaged cells are destroyed. Apart from physiological stimuli however, exogenous factors can induce apoptosis. Many anti-cancer drugs work by activating apoptosis in cancer cells. Natural substances have been found to have the ability to induce apoptosis in various tumour cells and these substances have been used as templates for the construction of novel lead compounds in anticancer treatment. On the other hand, alkylating agents such as cisplatin, cis- [PtCl2 (NH3) 2] have been widely used as antineoplastic agents for a wide variety of cancers including testicular, ovarian, neck and head cancers, amongst others. However, the use of cisplatin as an anticancer agent is limited due to toxicity and resistance problems. The aim of this present study was to screen the leaves of Rhus laevigata, a South African indigenous plant, for the presence of pro-apoptotic and anti-proliferative natural compounds and also to screen newly synthesised palladium based complexes (15 and 57) and a platinum based complex (58) for their antineoplastic activities tested against a panel of cell lines. Results. The results showed that crude methanol extracts from Rhus laevigata as well as the newly synthesised palladium based complexes (15 and 57) and a platinum based complex (58) induced apoptosis in the cell lines tested, as demonstrated by the externalization of phosphatidylserine, mitochondrial membrane permeabilization,caspase-3 activation, and DNA fragmentation. Caski (cervical cancer) and H157 (non small cell lung carcinoma) cell lines treated with the methanol extract from Rhus laevigata however, were more resistant to apoptosis induction. Among the metallocomplexes, complexes 15 and 57, palladium based complexes, were the most active. Conclusion: The methanol extract from the leaves of Rhus laevigata contain pro-apoptotic and antiproliferative natural compound(s), which need to be characterised and elucidated as they could provide the much-needed lead compounds in the fight against cancer. On the other hand the newly synthesized palladium complexes also need further evaluation to see if they can be used as anticancer agents that can overcome the problems associated with cisplatin. / South Africa

No description available.

Η ερευνητική προσπάθεια ανάπτυξης νέων αντινεοπλασματικών φαρμάκων, περιλαμβάνει μεταξύ άλλων και την τροποποίηση γνωστών χημειοθεραπευτικών ενώσεων, με σκοπό την ελάττωση των τοξικών τους παρανεργειών και τη βελτίωση της δραστικότητας των παραγώγων τους. Τέτοιες ενώσεις αποτελούν οι στεροειδικοί αλκυλιωτικοί παράγοντες, οι οποίοι αποτελούν και το αντικείμενο της παρούσας μελέτης. Ειδικότερα, μελετήθηκαν το προφίλ και η βιολογική δραστικότητα των χημικών αυτών ενώσεων έναντι της λευχαιμίας Ρ388, με απώτερο στόχο την προσπάθεια εξαγωγής Ποσοτικών Σχέσεων Δομής-Δράσης (QSAR). Αρχικά δημιουργήθηκε μια διαδραστική βάση δεδομένων-χημική βιβλιοθήκη, στην οποία περιελήφθησαν όλες οι πληροφορίες που αφορούν φυσικοχημικά χαρακτηριστικά και δεδομένα βιολογικής δραστικότητας των υπό μελέτη ενώσεων. Στη συνέχεια από τα δεδομένα της βάσης αυτής, συγκρίθηκαν μεταξύ τους και αναλύθηκαν διάφοροι συσχετισμοί μεταξύ των ενώσεων αυτών. Από την πρωταρχική μελέτη των ενώσεων που συμπεριλήφθηκαν στην βάση δεδομένων και εμφανίζουν αντινεοπλασματική δράση καθίσταται προφανές ότι άσχετα με το δοσολογικό σχήμα δραστικές έναντι της λευχαιμίας Ρ388 εμφανίστηκαν οι ίδιες (στην συντριπτική τους πλειοψηφία 43 έναντι 44 ανά κατηγορία δοσολογικού σχήματος) ενώσεις. Για τιμές λιποφιλικότητας LogP < 4, δεν καταγράφονται ενώσεις και αναγνωρίζεται μεγάλη ποικιλία συντεταγμένων, διότι είναι αρκετά δύσκολο να προκύψουν ενώσεις τόσο μικρής λιποφιλικότητας από το συνδυασμό στεροειδικού σκελετού και αλκυλιωτικού παράγοντα, εκτός αν προστεθούν στο στεροειδικό σκελετό και άλλες υδρόφιλες ομάδες. Από την παρούσα μελέτη προκύπτει ότι ο κατάλληλος συνδυασμός αλκυλιωτικού παράγοντα και στεροειδικού σκελετού οδηγεί σε ενώσεις υψηλής εκλεκτικότητας, ενώ η εισαγωγή στον Β δακτύλιο του στεροειδικού σκελετού του συζυγιακού συστήματος, οδηγεί κατά κανόνα σε μόρια υψηλής αντινεοπλασματικής ικανότητας και χαμηλής τοξικότητας. / -

Existem evidências crescentes indicando a associação entre dietas ricas em frutas e vegetais e a diminuição da incidência de câncer. O suco de laranja (OJ) pode ser incluído entre os alimentos com potencial quimioprotetor e seu estudo é muito relevante pelo amplo consumo desta bebida. O OJ possui vários nutrientes e compostos bioativos com atividades antioxidante, antimutagênica, anticarcinogênica e antiaterogênica, entre outras. A vitamina C (Vit C) é um dos nutrientes mais abundantes no OJ, e o único nutriente que pode ser provido em quantidade superior à recomendação diária por uma única porção de 200 mL de OJ. A Vit C, a exemplo de outros componentes do OJ, pode ser tanto benéfica quanto maléfica para os sistemas biológicos, dependendo do contexto metabólico. Neste sentido, vários nutrientes presentes no OJ têm sido identificados como mutagênicos ou carcinogênicos, especialmente quando administrados de forma isolada. Este estudo utilizou o ensaio Cometa alcalino em sangue de camundongos (in vivo) para avaliar: 1) a genotoxicidade do OJ e da Vit C; 2) a genotoxicidade do FeSO4 e do CuSO4: 3) o efeito modulador do OJ e da Vit C sobre a genotoxicidade do FeSO4 e CuSO4, bem como do metilmetanosulfonato (MMS) e da ciclofosfamida (CP). A versão alcalina do ensaio Cometa foi utilizada para avaliar o dano no DNA em células brancas do sangue periférico de camundongos. Adicionalmente, os níveis de cobre e ferro no sangue e no fígado dos camundongos tratados com metais e OJ foram avaliados pela metodologia de PIXE (Particle-Induced X-ray Emission). Grupos com pelo menos 6 camundongos (metade de cada sexo) foram tratados por gavage com uma ou duas doses de água (controle), CP, MMS, FeSO4 ou CuSO4. OJ (0.1 mL/Kg) foi administrado tanto antes (pré-tratamento) quanto após a administração das substâncias-teste (pós-tratamento). A Vit C (1 e 30 mg/Kg) foi administrada apenas no pós-tratamento. O dano no DNA foi avaliado 24 e 48 h após o início do tratamento. Após 24 h, o OJ induziu um suave aumento no dano no DNA, enquanto a Vit C foi genotóxica (30 mg/Kg > 1 mg/Kg). O tratamento duplo com Vit C (a 0 e a 24 h) induziu uma resposta genotóxica cumulativa a 48 h, que foi mais intensa para a dose maior. O FeSO4 e o CuSO4 foram genotóxicos após 24 h, mas tiveram seu dano efetivamente reparado após 48 h do tratamento. O pré-tratamento com OJ reduziu a genotoxicidade do FeSO4 e do CuSO4 (efeito preventivo). O pós-tratamento com OJ também reduziu a genotoxicidade do CuSO4 (efeito reparador). O OJ mostrou tanto efeito preventivo quanto reparador sobre a genotoxicidade do MMS. O OJ teve apenas efeito reparador sobre a CP. Ambas doses de Vit C aumentaram os danos no DNA causados pelo FeSO4 e pelo CuSO4. Adicionalmente, os níveis de cobre e ferro no sangue e no fígado dos camundongos tratados com metais e OJ foram avaliados pela metodologia de PIXE (Particle-Induced X-ray Emission). Grupos com pelo menos 6 camundongos (metade de cada sexo) foram tratados por gavage com uma ou duas doses de água (controle), CP, MMS, FeSO4 ou CuSO4. OJ (0.1 mL/Kg) foi administrado tanto antes (pré-tratamento) quanto após a administração das substâncias-teste (pós-tratamento). A Vit C (1 e 30 mg/Kg) foi administrada apenas no pós-tratamento. O dano no DNA foi avaliado 24 e 48 h após o início do tratamento. Após 24 h, o OJ induziu um suave aumento no dano no DNA, enquanto a Vit C foi genotóxica (30 mg/Kg > 1 mg/Kg). O tratamento duplo com Vit C (a 0 e a 24 h) induziu uma resposta genotóxica cumulativa a 48 h, que foi mais intensa para a dose maior. O FeSO4 e o CuSO4 foram genotóxicos após 24 h, mas tiveram seu dano efetivamente reparado após 48 h do tratamento. O pré-tratamento com OJ reduziu a genotoxicidade do FeSO4 e do CuSO4 (efeito preventivo). O pós-tratamento com OJ também reduziu a genotoxicidade do CuSO4 (efeito reparador). O OJ mostrou tanto efeito preventivo quanto reparador sobre a genotoxicidade do MMS. O OJ teve apenas efeito reparador sobre a CP. Ambas doses de Vit C aumentaram os danos no DNA causados pelo FeSO4 e pelo CuSO4. processado e armazenado de forma a preservar o seu potencial biológico é um alimento sugerido como uma das porções de uma dieta equilibrada (contendo pelo menos 5 porções de frutas e vegetais), recomendada para uma vida saudável e longeva. / Evidence indicates an association between diets rich in fresh fruit and vegetables and a decreased incidence of cancers. Orange juice (OJ) is a food with chemoprotective potential highly relevant for study due to its widespread consumption. OJ is composed of several nutrients and bioactive compounds with antioxidant, antimutagenic, anticarcinogenic and antiathrerogenic activities. Vitamina C (Vit C) is the most abundant nutrient in OJ, and the only one that can be provided in amounts higher that the daily recommended intake by a single portion of OJ (200 mL). Vit C, like other components of OJ, can be either benefical or noxious for biological system, depending of their metabolic context. Indeed, some components of juices have been identified as mutagenic or carcinogenic when isolated. In this study we tested by comet assay in mice in vivo: 1) the genotoxicity of orange juice (OJ) and vitamin C (Vit C); 2) the genotoxicity of FeSO4 and CuSO4: 3) the modulator effect of orange juice and Vit C over genotoxicity of FeSO4 and CuSO4, as well as over methyl methanesulfonate (MMS) and cyclophosphamide (CP). We used the alkaline version of the comet assay to assess DNA damage in peripheral white blood cells of mice. Moreover, the levels of iron and copper in the whole blood and liver of the mice treated with this metals were evaluated by PIXE (Particle-Induced X-ray Emission). Groups of at least 6 mice (half of each gender) were orally given a single dose of either water (control), CP, MMS, FeSO4 or CuSO4. OJ (0.1 mL/Kg) was given either before (pre-treatment) or after (post-treatment) administration of the test substances. Vit C (1 and 30 mg/Kg) was only administered after treatment (post-treatment). DNA damage was evaluated 24 and 48 h after the beginning of the treatment. After 24 h, OJ induced a slight increase in DNA damage and Vit C was genotoxic (30 mg/Kg > 1 mg/Kg). Double treatment with Vit C (at 0 and 24 h) induced a cumulative genotoxic response at 48 h, more intense for the higher dose. FeSO4 and CuSO4 were genotoxic after 24 h and significant DNA damage repair was observed after 48 h of treatment. OJ pre-treatment reduced the genotoxicity of FeSO4 (preventive effect). OJ had a preventive effect over the genotoxicity of CuSO4. OJ post-treatment also reduced the genotoxicity of CuSO4 (restorative effect). OJ had both protective and reparative effects over MMS. OJ had only a reparative effect over CP. Both doses of Vit C enhanced DNA damage caused by FeSO4 and CuSO4. DNA damage caused by MMS was significantly reduced by the lower dose, but not by the higher dose of Vit C. For CP, the DNA damage was not affected by the post-treatment with any of the doses of Vit C. PIXE analysis indicated a positive correlation between DNA damage and the hepatic levels of iron and a negative correlation between whole blood copper and DNA damage. A negative correlation between hepatic iron and whole blood copper content was also seen in the treatment with both ferrous and cupric sulfates. These results point a dynamic interaction between the genotoxicity and the tecidual fate of iron and copper. Vit C and the other components of OJ have several biological effects, including: 1) action as targets for toxicants; 2) influence in drug metabolization/detoxification; and 3) effect in DNA repair and homeostasis. Moreover, Vit C and transition metals, particularly copper and iron, can induce oxidative stress; however, they can also play roles in antioxidant defense system, being a DNA repair modulators. Further data from other treatment schedules are needed to shed light upon the beneficial/noxious effects of OJ as a complex mixture, as well as of its compounds in genomic stability. Indeed, one glass of fresh or adequate processed and stored OJ can be among the options for the daily 5 portions (or even more) of fruits and vegetables recommended for a health and longevity.