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 toeffectively enhancethe effect of ionizing radiation (10). Similarly, inhibitorshave been sought for ataxia telangiectasia mutated (ATM), which acts as asensor of DSBs and activates p53 and other components of the DNA damageresponse like BRCA1 (11,12).Screening of a small molecule inhibitor library led to the identification ofKU-55933 as an inhibitor of ATM (13). KU-55933 was found toenhance radiosensitivity as well as chemosensitivity to doxorubicin andcamptothecin (13,14).Polynucleotide kinase/phosphatase (PNKP) is arelatively new target in the field of DNA repair inhibition by small molecules.

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We previously observed that shRNA-mediated depletion of PNKP sensitizes cells toradiation and chemotherapy such as the Top I poison camptothecin (15). The first inhibitor, A12B4C3, of the DNA3?-phosphatase activity of PNKP was shown to sensitize acute myeloid leukemia(AML) cells, A549 lung carcinoma and MDA-MB-231 breast cancer cells to ?-radiationand camptothecin (16-18). Modifications have been made to A12B4C3that resulted in the synthesis of A12B4C50 and A83B4C63.

The second generationof A12B4C3 has been shown to be more potent than the parent compound (refer toChapters 2 and 3).  Although small molecules are greatadvancement to cancer therapy, there remain significant challenges to thetreatment of cancer by small molecule inhibitors. 1) In many solid tumors thereare many genetic mutations so inhibiting a single pathway may not result in asignificant therapeutic effect. 2) The small molecule inhibitors may causetoxic side effects to normal tissues. 3) Factors such as increased interstitialfluid pressure of tumors may make the uptake of therapeutic agents lessefficient (19).

One of the mostpromising ways of meeting such challenges is ligand-targeted therapy that maybe used to make targeting more specific and carry higher dosages of anti-cancerdrug to tumor tissue. Therefore, optimum combination therapy regimens with noveldelivery approaches are needed to eliminate challenges hindering small moleculedrugs.

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