Bases do Tratamento Quimioterápico
Autor: SPRS/PreparandoproTEP | Publicado: 2012-09-21T06:29:00-07:00

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Profa Dra Cecília Fernandes Lorea *



O câncer
infantil é uma doença rara que corresponde a, aproximadamente, 3% de todos os
cânceres, mas é a primeira causa morte por doença em crianças maiores de 1 ano
de idade. Pela raridade, atualmente, os tratamentos são desenvolvidos em
protocolos de grupos cooperativos internacionais que estudam em conjunto as
bases fisiopatológicas de cada neoplasia e desenvolvem esquemas de tratamento
utilizando terapia multidroga e multimodal.

A
quimioterapia foi introduzida para tratamento da leucemia na infância na década
de 40. Desde então o prognóstico das crianças com câncer têm melhorado dramaticamente,
aumentando para 78% a taxa de sobrevida global de uma doença que, na era pré
quimioterapia era uniformemente fatal. Assim, a terapia multimodal que integra
cirurgia, radioterapia e quimioterapia foi incorporada no tratamento das
neoplasias infantis. Com a melhora da sobrevida, estudos visando reduzir
efeitos colaterais da terapia antineoplásica, utilizando-se mais dos diversos
agentes quimioterápicos e reduzindo dose e indicações de radioterapia e
diminuindo necessidade de cirurgias mutiladoras com uso pré cirúrgico das
drogas.

As drogas
anticâncer são usadas na infância nas diversas vias de administração:
endovenosa, subcutânea, intramuscular, oral entre outras. As drogas como
metotrexate, citarabina e tiotepa podem também ser utilizadas por administração
intratecal e desta forma previnem e tratam infiltração neoplásica do sistema
nervoso central, diminuindo uso de radioterapia em crânio e neuroeixo em
doenças como linfoma e leucemia.

A estratégia
de erradicação do câncer é baseada no modelo de sucesso que é a cura das
infecções bacterianas. Ela visa explorar as diferenças entre o câncer e as
células normais do hospedeiro, e erradicar todas as células cancerígenas do
corpo. Este paradigma teve um impacto profundo na descoberta, desenvolvimento e
desenho dos tratamentos antineoplásicos.

As primeiras
drogas usadas e seus mecanismos de ação foram identificados após a verificação
clínica de melhora da doença, portanto a maioria é citotóxica não seletiva e
produz toxicidade substancial. Apesar dos avanços na pesquisa básica terem
promovido vários “insights” sobre a patogênese do câncer infantil, a maioria
das drogas utilizadas possuem mecanismos de ação não seletivos que tem com alvo
macromoléculas (ex. DNA) ou rotas metabólicas criticas para proliferação
celular, tanto das células malignas como das normais, produzindo um efeito
citotóxico severo indesejado.


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Mecanismo de ação das diversas drogas
antitumor (baseado em figura Pizzo e Popplack, 5a Edição, 2006)



Para
explicitar os mecanismos de ação dos quimioterápicos utilizados separamos eles
em grupos. São eles:

·&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
Agentes alquilantes (ex. Ciclofosfamida,
Ifosfamida, Cisplatina): são quimicamente reativos a compostos que lesam o DNA.
Através de pontes e ligações cruzadas com as nucleobases, bloqueio da síntese
de antimetabólitos ou incorporando bases fraudulentas ao DNA impedem sua
duplicação, com consequente parada na proliferação celular.

·&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
Antimetabólitos (ex. Metotrexate,
Mercaptupurina, Citarabina): são análogos estruturais de cofactores vitais ou
intermediários das rotas de biosíntese do DNA e do RNA, produzindo um produto
defeituoso que causa bloqueio da reprodução celular.

·&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
Antibióticos antitumor (ex. Doxorrubicina,
Belomicina): são produtos naturais que foram originalmente isolados de uma
variedade de microorganismos que se ligam avidamente ao DNA por intercalação,
entrando no interior da dupla hélice do DNA clivando-a e religando-a, causando,
assim, destruição celular.

·&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
Produtos de plantas (ex. Vincristina, Etoposide,
Topotecam): derivados de plantas e suas toxinas com mecanismo de ação complexo
que foram parcialmente definidos agindo como inibidores mitóticos ou causando
quebras no DNA ou agindo com radiosensibilizador.

·&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
Outros agentes com mecanismos de ação diversos
que agem como drogas antineoplásicas. Temos com exemplo os corticosteróides que
devem ser usados com muito cuidado na prática diária, pois podem agir
promovendo remissão não duradoura da neoplasia diminuindo, assim, chance de
cura por recidiva precoce devido à terapia ineficaz. Outras drogas também foram
incorporadas ao tratamento antineoplásico como: Asparaginase (derivado da Escherichia coli ou Erwinia carotovara) usado na leucemia linfóide aguda e linfoma
linfoblástico; Retinóides usado na leucemia promielocítica (com objetivo de
maturar a célula blástica) e no neuroblastoma alto risco; Mesilato de Imatinibe
agente com mecanismo de ação contra células que expressam cromossomo
Philadelphia.



Outras
medicações com atividade antitumor específicas tem sido desenvolvidas como o
Rituximab, droga que age contra as células com marcados de superfície CD20. A
maioria ainda não foram liberadas para uso nas crianças por serem de descoberta
recente.



*Professora Assistente Universidade Federal de Pelotas