overexpressed shown to be more potent than the

overexpressed in non-small cell lung cancer
(NSCLC) and is considered to contribute to radioresistance (9). NU7441 has been shown to
effectively enhance
the effect of ionizing radiation (10). Similarly, inhibitors
have been sought for ataxia telangiectasia mutated (ATM), which acts as a
sensor of DSBs and activates p53 and other components of the DNA damage
response like BRCA1 (11,
12).
Screening of a small molecule inhibitor library led to the identification of
KU-55933 as an inhibitor of ATM (13). KU-55933 was found to
enhance radiosensitivity as well as chemosensitivity to doxorubicin and
camptothecin (13,
14).

Polynucleotide kinase/phosphatase (PNKP) is a
relatively new target in the field of DNA repair inhibition by small molecules.
We previously observed that shRNA-mediated depletion of PNKP sensitizes cells to
radiation and chemotherapy such as the Top I poison camptothecin (15). The first inhibitor, A12B4C3, of the DNA
3?-phosphatase activity of PNKP was shown to sensitize acute myeloid leukemia
(AML) cells, A549 lung carcinoma and MDA-MB-231 breast cancer cells to ?-radiation
and camptothecin (16-18). Modifications have been made to A12B4C3
that resulted in the synthesis of A12B4C50 and A83B4C63. The second generation
of A12B4C3 has been shown to be more potent than the parent compound (refer to
Chapters 2 and 3). 

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Although small molecules are great
advancement to cancer therapy, there remain significant challenges to the
treatment of cancer by small molecule inhibitors. 1) In many solid tumors there
are many genetic mutations so inhibiting a single pathway may not result in a
significant therapeutic effect. 2) The small molecule inhibitors may cause
toxic side effects to normal tissues. 3) Factors such as increased interstitial
fluid pressure of tumors may make the uptake of therapeutic agents less
efficient (19). One of the most
promising ways of meeting such challenges is ligand-targeted therapy that may
be used to make targeting more specific and carry higher dosages of anti-cancer
drug to tumor tissue. Therefore, optimum combination therapy regimens with novel
delivery approaches are needed to eliminate challenges hindering small molecule
drugs.

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