BCR-ABL antisense oligodeoxyribonucleotides suppress the growth of leukemic and normal hematopoietic cells by a sequence-specific but nonantisense mechanism.

We have examined the effect of BCR/ABL junctional antisense phosphodiester oligodeoxyribonucleotides (ODNs) on BV173 and other chronic myeloid leukemia (CML) cell lines. Various control ODNs were used to understand the mechanism of the observed antiproliferative effect. Not only the antisense ODNs but also several control ODNs inhibit the proliferation of the leukemic cell lines. All the ODNs that inhibit the cell proliferation share a TAT consensus sequence at their 3' end. A 1-base mismatch within this consensus sequence abolishes the antiproliferative effect. Mismatches of several bases at any other position within the sequence of the active ODNs do not suppress the observed effect. Similar experiments on normal or CML CD34+ cell fraction led to the same observations. We conclude that the antiproliferative effect of the phosphodiester BCR/ABL antisense ODNs cannot be attributed to an antisense mechanism but rather to a nonelucidated effect of a 3' terminal TAT sequence. This effect is not CML specific.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Antisense oligodeoxyribonucleotides suppress hematologic cell growth through stepwise release of deoxyribonucleotides.

Antisense oligodeoxyribonucleotides (ODNs) are now being extensively investigated in an attempt to achieve cell growth suppression through specific targeting of genes related to cell proliferation, despite increasing evidence of non-antisense cytotoxic effects. In the context of anti-BCR/ABL antisense strategies in chronic myeloid leukemia, we have reexamined the antiproliferative effect of phosphodiester and phosphorothioate ODNs on the leukemic cell line BV173 and on CD34+ bone marrow cells in liquid culture. The 3' sequences of the ODNs determine their effect. At concentrations of 10 micromol/L (for phosphorothioate ODNs) or 25 micromol/L (for phosphodiester ODNs), all the tested ODNs exert an antiproliferative activity, except those that contain a cytosine residue at either their two most terminal 3' positions. We show that this antiproliferative effect is due to the toxicity of the d-NMPs (5' monophosphate deoxyribonucleosides), the enzymatic hydrolysis products of the ODNs in culture medium. The toxicity of the d-NMPs on hematologic cells depends on their nature (d-CMP [2'deoxycytidine 5'-monophosphate] is not cytotoxic), on their concentration (d-GMP [2'-deoxyguanosine 5'-monophosphate], TMP [thymidine 5'-monophosphate], and d-AMP [2'-deoxyadenosine 5'-monophosphate] are cytotoxic at concentrations between 5 and 10 micromol/L), and on the coincident presence of other d-NMPs in the culture medium (d-CMP neutralizes the toxicity of d-AMP, d-GMP, or TMP). The antiproliferative activity of ODNs is thus restricted to conditions where the 3' hydrolysis process by exonucleases generates significant amounts of d-NMPs with a low proportion of d-CMP. Our results reveal a novel example of a nonantisense effect of ODNs, which should be taken into account when performing any experiment using assumed antisense ODNs.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Inclusão escolar e deficiência mental: análise da interação social entre companheiros School inclusion and mental deficiency: analysis of the social interaction among peers

A inclusão escolar de portadores de deficiências tem sido a proposta norteadora e dominante na Educação Especial no Brasil nos últimos anos. Esta pesquisa teve por objetivo descrever e analisar a interação social entre três alunos das primeiras séries do Ensino Fundamental com Deficiência Mental (DM) e seus colegas, em três escolas-pólos municipais de Vitória, ES. Aplicaram-se a todos 80 alunos testes sociométricos com perguntas sobre três escolhas e três rejeições para brincar e realizar tarefas escolares; foram filmadas 15 sessões de observações na situação de recreio, cinco para cada um dos três sujeitos focais. Esses dados foram compatíveis com aqueles obtidos nos testes sociométricos, mostrando que esses os alunos com DM são menos aceitos e são mais rejeitados do que seus colegas, passando a maior parte do tempo de recreio sozinhos, demonstrando dificuldades para iniciar, manter e finalizar os contatos sociais com os colegas.<br>The inclusion of bearers of deficiencies in schools has been a guiding and dominating proposal in Special Education, including in Brazil, and has directed rehabilitation and educational programs and policies. The aim of this study was to describe and to analyze the interaction among three students with Mental Retardation (MR) and their peers. The study was carried out with first-grade students of three core municipal schools of the city of Vitória, ES, Brazil, who had classmates who were bearers of MR. All 80 students were given a sociometric test containing questions on three choices and rejections of classmates with whom to play and to accomplish classroom tasks. Fifteen observation sessions were recorded, five for each target children (plus an extra one for one of the children), during an entire month. The results showed that students who have special education needs are less frequently accepted and more frequently rejected than their peers in regular classrooms. It was noted that subjects spent most of their time alone, showing difficulties in initiating, maintaining and finalizing contacts with their classmates