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Abstract(s)
O 5-Fluorouracil (5-FU) tem sido um importante fármaco anticancerígeno até à data. É um dos
fármacos citotóxicos mais utilizados em vários tipos de cancro, como os gastrointestinais, da
mama, da pele, da cabeça e do pescoço, e pode ser administrado por via intravenosa ou tópica,
dependendo do tipo de cancro e da região a tratar. Após a sua ativação, os metabolitos do 5-FU
podem exercer efeitos citotóxicos através da inibição da timidilato sintetase (TS), ou através da
sua incorporação no RNA e DNA, eventos que acabarão por induzir citotoxicidade e morte
celular. Apesar da sua elevada aplicabilidade, está comummente associada a efeitos secundários
adversos que podem comprometer a sua utilização, como por exemplo cardiotoxicidade,
mielossupressão, mucosite intestinal, diarreia grave e até o desenvolvimento de resistências à
quimioterapia. Com o aumento do conhecimento do seu mecanismo de ação, foram
desenvolvidas nas últimas décadas várias estratégias para aumentar a sua atividade
anticancerígena e colmatar as suas desvantagens, que incluem a modificação química, o que
deu origem a novas moléculas químicas, e a implementação de regimes baseados em análogos
de 5-FU. Os pró-fármacos de 5-FU, por exemplo, capecitabina, tegafur, apresentam alterações
químicas concebidas para serem melhor absorvidos através da mucosa gastrointestinal e
aumentar a biodisponibilidade de 5-FU numa dose terapêutica mais baixa. Outra estratégia que
está a receber atenção no tratamento do cancro é a sua associação a sistemas de veiculação de
fármacos, com o objetivo de modular o seu perfil de biodistribuição. Alguns dos sistemas de
veiculação de fármacos focados no presente trabalho foram os lipossomas, com alta afinidade
por membranas biológicas; os niossomas, com alta estabilidade química; os transferssomas,
com estrutura ultra-deformável; os etossomas, utilizando etanol como co-solvente; as
microemulsões, altamente estáveis termodinamicamente; as microesponjas, com sua superfície
altamente porosa; e as microagulhas. Outras formulações estão ainda a ser concebidas e
testadas, como uma folha de duas camadas para a libertação controlada e local do fármaco por
exemplo no cancro do pâncreas.
De um modo geral, as estratégias descritas no presente trabalho pretendem melhorar o índice
terapêutico do importante fármaco anticancerígeno, o 5-FU.
5-Fluorouracil (5-FU) has been an important anti-cancer drug to date. It is one of the cytotoxic drugs most used in various types of cancer, such as gastrointestinal, breast, skin, head and neck, and can be administered intravenously or topically, depending on the type of cancer and region meant for treatment. After activation, 5-FU metabolites can exert cytotoxic effects via inhibition of thymidylate synthetase (TS), or through incorporation into RNA and DNA, events that will ultimately induce cytotoxicity and cell death. Despite having a high applicability, it is commonly associated to severe side effects that may compromise its use, for instance cardiotoxicity, myelosuppression, intestinal mucositis, severe diarrhoea and even the development of chemoresistance. With an increase in the knowledge of its mechanism of action, various treatment modalities have been developed over the past few decades to increase its anti cancer activity while diminishing its disadvantages, which include the chemical modification being in the origin of new analogues of 5-FU. 5-FU prodrugs, such as capecitabine and tegafur, have a variety of chemical alterations designed to be better absorbed through the gastrointestinal mucosa and to increase the bioavailability of 5-FU at a lower therapeutic dose. Another strategy that is receiving attention in cancer treatment is its association to drug delivery systems (DDS), aiming to modulate its biodistribution profile. Some of the DDS focused in the present work were liposomes, with high affinity for biological membranes; niosomes, with high chemical stability; transfersomes, with an ultra-deformable structure; ethosomes, using ethanol as cosolvent; microemulsions, highly thermodynamically stable; microsponges, with its highly porous surface; and microneedles. Other formulations are still being designed and tested, such as a two-layered sheet for the controlled and local release of the drug in pancreatic cancer. Overall, the described strategies in the present work intend to improve the therapeutic index of the important anticancer drug, the 5-FU.
5-Fluorouracil (5-FU) has been an important anti-cancer drug to date. It is one of the cytotoxic drugs most used in various types of cancer, such as gastrointestinal, breast, skin, head and neck, and can be administered intravenously or topically, depending on the type of cancer and region meant for treatment. After activation, 5-FU metabolites can exert cytotoxic effects via inhibition of thymidylate synthetase (TS), or through incorporation into RNA and DNA, events that will ultimately induce cytotoxicity and cell death. Despite having a high applicability, it is commonly associated to severe side effects that may compromise its use, for instance cardiotoxicity, myelosuppression, intestinal mucositis, severe diarrhoea and even the development of chemoresistance. With an increase in the knowledge of its mechanism of action, various treatment modalities have been developed over the past few decades to increase its anti cancer activity while diminishing its disadvantages, which include the chemical modification being in the origin of new analogues of 5-FU. 5-FU prodrugs, such as capecitabine and tegafur, have a variety of chemical alterations designed to be better absorbed through the gastrointestinal mucosa and to increase the bioavailability of 5-FU at a lower therapeutic dose. Another strategy that is receiving attention in cancer treatment is its association to drug delivery systems (DDS), aiming to modulate its biodistribution profile. Some of the DDS focused in the present work were liposomes, with high affinity for biological membranes; niosomes, with high chemical stability; transfersomes, with an ultra-deformable structure; ethosomes, using ethanol as cosolvent; microemulsions, highly thermodynamically stable; microsponges, with its highly porous surface; and microneedles. Other formulations are still being designed and tested, such as a two-layered sheet for the controlled and local release of the drug in pancreatic cancer. Overall, the described strategies in the present work intend to improve the therapeutic index of the important anticancer drug, the 5-FU.
Description
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2023, Universidade de Lisboa, Faculdade de Farmácia.
Keywords
5-Fluoruracil Cancer Drug delivery systems Mestrado Integrado - 2023