Compositions and methods of treating neoplasia
The invention features compositions and methods that are useful for the treatment of neoplasia by reducing base excision repair (BER). Such compositions are useful, for example, for enhancing the efficacy of known chemotherapeutics, such as DNA alkylating agents. In particular, the invention features agents that mimic the interaction of APC with pol-β. Such agents reduce the activity of long patch- and single nucleotide-base extension repair pathways.
1. A method for treating colon cancer in a subject, the method comprising administering to said subject an effective amount of temozolamide and NSC-124854 having the following structure:
thereby treating the colon cancer.
2. The method of claim 1 , wherein NSC-124854 binds polβ at an adenomatous polyposis coli (APC) binding site comprising amino acids Thr79, Lys81 and Arg83, and reduces pol-β-directed dRP-lyase activity or pol-β-directed strand-displacement synthesis, thereby treating the colon cancer.
3. The method of claim 1 , wherein NSC-124854 binds polβ at an adenomatous polyposis coli (APC) binding site comprising polβ amino acids selected from the group consisting of amino acids 60-120, 60-170, and 80-170.
4. A method for treating colon cancer in a subject, the method comprising administering to said subject an effective amount of NSC-124854 having the following structure:
, and temozolamide, wherein the effective amount of NSC-424854 and temozolomide has reduced toxicity relative to the administration of an effective amount of temozolamide alone, thereby treating the colon cancer.
5. The method of claim 1 , wherein the subject is identified as having a colon cancer that does not respond to a conventional chemotherapeutic or that is DNA mismatch repair deficient.
6. The method of claim 1 , wherein the method further comprises the step of identifying the subject as having an MMR-deficient colon cancer or a colon cancer that does not respond to conventional chemotherapeutics.
7. The method of claim 6 , wherein an effective amount of NSC-124854 and temozolomide has reduced toxicity relative to the administration of an effective amount of temozolamide alone.
8. A pharmaceutical composition for the treatment of colon cancer, the composition comprising an effective amount of NSC124854
having the following structure:
and temozolomide.