Thus, it supports the rational of combining UV B the site radi ation and ZD6474 in treating breast cancer cells. More over, it was found that 5 flurouracil, an anti cancer drug with ionizing radio Inhibitors,Modulators,Libraries sensitization activity, also enhanced the UV B mediated apoptosis in breast cancer. Pre viously it was shown that dual targeting of EGFR and VEGFR in combination with RT enhanced antitumor ac tivity of lung cancer in vivo as compared to either agent alone. Considering these previous findings, it is likely that EGFR and VEGFR TKI ZD6474, when combined with UV B phototherapy, will improve tumor control and provide wider applicability. The mechanisms by which tumor response to UV B radiation is enhanced by ZD6474, Inhibitors,Modulators,Libraries however, are not currently understood.

In our study using in vitro breast cancer cells MCF 7 and MDA MB 468 that closely recapitulates breast can cer with lower and higher VEGF expression respectively, we found that ZD6474 substantially improved radio response to UV B in both Inhibitors,Modulators,Libraries cell lines. The radio sensitivity to UV B was 2 fold in higher expressed VEGF produ cing MDA MB 231 and MDA MB 468 when treated with 1 uM ZD6474 in combination with UV B. The mechanism underlying the decrease in cell viability following combination treatment with ZD6474 and UV B was studied. The photomicrograph of MCF 7 and MDA MB 468 irradiated with increasing doses of UV B clearly demonstrated the involvement of apoptosis in de creasing cell viability with lesser involvement of antiproliferative effects, which was further Inhibitors,Modulators,Libraries confirmed from cell counts using trypan blue dye exclusion assays.

It was shown earlier Inhibitors,Modulators,Libraries that UV radiation induced apop tosis as compared to ionizing radiation that mainly in duced cell cycle arrest in osteosarcoma in vitro. Moreover the extent of DNA damage, cell type, and ge netic alterations determined the cells tissues response to radiation to undergo either apoptosis or cell cycle arrest. Hence, the elucidation of the mechanism of UV induced apoptosis in breast cancer will be important to make a rational decision for combining UV B radiation with chemotherapeutic agents or small inhibitors e. g.TKI. In contrast to UV B, ZD6474 is more an antiproliferative agent than a cytotoxic agent at its lower concentration. The enhanced activity of ZD6474 in decreasing cell viability may be contributed both due to anti proliferative and apoptotic effects of combination treat ment.

ZD6474 significantly potentiates the apoptotic activity of UV B as shown by flow cytometry. Formation of oligonucleosomes or fragmented DNA, membrane blebbing further confirmed that cell death was due to activation of the apoptotic pathway as shown selleck catalog in Figure 4. Our findings have shown that ZD6474 may improve the therapeutic index for UV B photothe rapy by enhancing tumor specific cytotoxicity.