Chemotherapy is a common treatment for a variety of cancers. Chemotherapeutic alkylating agents represent a key category of commonly used antineoplastic drugs. These drugs are active against chronic leukemias, non-Hodgkin lymphoma, Hodgkin disease, multiple myeloma, lung, breast, ovarian cancer, and certain other cancers. The DNA repair protein, O6-alkylguanine-DNA alkyltransferase (AGT), is a primary source of tumor cell resistance to the alkylating drugs that alkylate the O6 position of guanine in DNA. AGT therefore becomes the prime target for modulation. Currently, AGT inactivators are used as adjuvants to enhance chemotherapy by the alkylating drugs.

O6-Benzylguanine is the prototype AGT inactivator in phase I, II and III clinical trials as an adjuvant to improve chemotherapy. Although O6-benzylguanine is a promising AGT inactivator, it is not an ideal drug. O6-Benzylguanine is only sparingly soluble in water, and it is not effective in inactivating some mutant alkyltransferase proteins that could possibly be produced after repeated chemotherapy cycles. The present invention describes oligodeoxyribonucleotides containing O6-benzylguanine residues as another class of AGT inactivators, and discusses the advantages of their use in comparison to O6-benzylguanine as the free base. Oligodeoxyribonucleotides containing O6-benzylguanine residues are extremely water soluble and can efficiently inactivate AGT at much lower concentrations than O6- benzylguanine. In addition, they are effective in inactivating several mutant alkyltransferase proteins that are highly resistant to inactivation by O6-benzylguanine. Furthermore, positioning O6-benzylguanine near the 3'- or 5'- terminus of these oligodeoxyribonucleotides improves their resistance to degradation by cellular nuclease proteins. Therefore, oligodeoxyribonucleotides containing multiple O6- benzylguanine residues may be more effective chemotherapy adjuvants than O6-benzylguanine.

U.S. Patent No. 6,060,458 issued 09 May 2000 (HHS Reference No. E-104-1998/0-US-01)

Inventors: Robert Moschel et al. (NCI)

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