Oligodeoxyribonucleotides comprising o6-benzylguanine and...

C - Chemistry – Metallurgy – 07 – H

Patent

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C07H 21/00 (2006.01) A61K 31/70 (2006.01) C07H 21/04 (2006.01)

Patent

CA 2320288

The present invention provides a single-stranded oligodeoxyribonucleotide, which (i) comprises from about 5 to 11 bases, at least one of which is a substituted or an unsubstituted O6-benzylguanine, and (ii) inactivates human AGT. The present invention also provides a single-stranded oligodeoxyribonucleotide, which can inactivate a mutant human AGT, which either is not inactivated by O6-benzylguanine or is less inactivated by O6- benzylguanine than by said single-stranded oligodeoxyribonucleotide. A phosphate of the single-stranded oligodeoxyribonucleotide can be replaced by a methylphosphonate or a phosphorothioate. The present invention also provides a composition comprising such an oligodeoxyribonucleotide. In addition, the present invention provides a method of enhancing the effect of an antineoplastic alkylating agent, which alkylates the O6 position of guanine residues in DNA, in the chemotherapeutic treatment of cancer in a mammal, which method comprises the co-administration to the mammal of a cancer- treatment effective amount of an antineoplastic alkylating agent and a chemotherapeutic treatment-enhancing amount of a present inventive oligodeoxyribonucleotide or composition thereof.

La présente invention concerne un oligodésoxyribonucléotide à brin unique qui [i] comprend environ 5 à 11 bases dont au moins une est un O?6¿-benzylguanine substitué ou non substitué et [ii] désactive l'AGT (O?6¿-alkylguanine-ADN alkyltransférase) humaine. La présente invention concerne également un oligodésoxyribonucléotide à brin unique capable de désactiver une AGT humaine mutante, qui soit n'est pas désactivée par O?6¿-benzylguanine ou est moins désactivée par O?6¿-benzylguanine que par l'oligodésoxyribonucléotide à brin unique. On peut remplacer un phosphate de l'oligodésoxyribonucléotide à brin unique par un méthylphosphonate ou un phosphorothioate. La présente invention concerne aussi une composition comprenant cet oligodésoxyribonucléotide. En outre, la présente invention concerne un procédé d'amélioration de l'effet d'un agent d'alkylation antinéoplasique, qui effectue l'alkylation de la position O?6¿ de résidus de guanine dans l'ADN dans le traitement chimiothérapeutique du cancer chez un mammalien, ce procédé consistant à co-administrer au mammalien une quantité effective contre le cancer d'un agent d'alkylation antinéoplasique et une quantité d'un oligodésoxyribonucléotide de la présente invention ou d'une composition le comprenant, permettant d'améliorer le traitement chimiothérapeutique.

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