3 8. 96 mm2 and 48. 6 30. 1 mm2, respectively. However, the average tumor size in the right mammary gland treated with T oligo and 3Gy IR was reduced to 8. 67 3. 61 mm2, compared with the http://www.selleckchem.com/products/Dasatinib.html average tumor size of 27. 67 8. 69 mm2 in the left mammary gland treated with control oligo and 3 Gy IR. This reduc tion in tumor size was highly statistically significant. The reduction in tumor size is more than the combined reduction by the treatment of T oligo or radia tion alone when compared with those in the no treat ment group. Consistent with the observed reduction in tumor size, there was a striking increase in TUNEL posi tive cells 10 days post irradiation in T oligo treated tumors. Taken together, these results indi cate that an additive or synergistic effect of T oligo and radiation therapy can be achieved in a murine model that is closely related to breast cancer in humans.

Ionizing radiation induces both single and double strand DNA breaks in cells that then trigger DNA damage responses characterized by the recruitment of DNA repair proteins to gH2AX foci at sites Inhibitors,Modulators,Libraries of DNA damage and the activation of checkpoint proteins that arrest cell cycle pro gression. Cell cycle arrest is a protective cellular response understood to block cell cycle progression and to permit DNA damage repair. An increase in DNA damage, reduced ability to repair DNA damage, and or prolonged checkpoint activation Inhibitors,Modulators,Libraries Inhibitors,Modulators,Libraries can cause apoptosis or cause cells to undergo permanent cell cycle arrest. We show here that pretreatment with T oligo sensitizes mammary tumor cells to radiation, pro moting growth inhibition and death of tumor cells in vitro and in an in vivo mouse model.

The mechanism by which T oligo sensitize tumor cells remains to be fully elucidated. Although T oligos do not act as telomerase inhibitors or cause digestion of the 3 telomere overhang, T Inhibitors,Modulators,Libraries oligos have been shown to rapidly concentrate Inhibitors,Modulators,Libraries in nuclei when added to cultured cells and the subsequent responses require WRN, the protein mutated in the progeroid cancer prone Werner syndrome. T oligo WRN interaction results in formation of DNA gH2AX damage like foci at the telomeres with activation of ATM and its many downstream effector proteins, leading to apoptosis and senescence. In the present study, pretreat ment with T oligo enhances the formation of gH2AX foci that customarily form at sites of DNA damage but after T oligo treatment form at telomeres in the absence of detectable DNA damage.

Activating the DNA damage response pathways by T oligo treat ment, as demonstrated to occur over several days in multiple cell types including breast carcinoma cells, could render tumor cells more apt to undergo apoptosis or senescence when exposed to nevertheless IR. Alterna tively, tumor cell inactivation could be due to the impairment of DNA repair by the pretreatment with T oligo as demonstrated by slower decay of gH2AX foci and increased fragmentation of DNA in the comet assay.