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Elsewhere, we reported that multiple serial in vivo passage of a squamous cell carcinoma cells

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Recently, nanoparticles have been considered as a method of providing radiation dose enhancement in tumors. In order to quantify this affect, a dose enhancement factor (DEF) is defined that represents the ratio of the dose deposited in tumor with nanoparticles, divided by the dose deposited in the tumor without nanoparticles. Materials with atomic numbers (Z) ranging from 25 to 90 are considered in this analysis. In addition, the energy spectrum for a number of external beam x-ray sources and common radionuclides are evaluated. For a nanoparticle concentration of 5 mg/ml, the DEF is < 1.05 for Co-60, Ir-192, Au-198, Cs-137, 6, 18, and 25 MV x-rays for all materials considered. However, relatively large increases in the DEF are observed for 50, 80, 100, and 140 KVp x-rays as well as Pd-103 and I-125. The DEF increases for all sources as Z varies from 25-35. From Z = 40-60, the DEF plateaus or slightly decreases. For higher Z materials (Z>70), the DEF increases and is a maximum for the highest Z materials. High atomic number nanoparticles coupled with low energy external beam x-rays or brachytherapy sources offer the potential of significantly enhancing the delivered dose.

Persistent DNA double-strand breaks (DSB) may determine the antitumor effects of ionizing radiation (IR) by inducing apoptosis, necrosis, mitotic catastrophe, or permanent growth arrest. IR induces rapid modification of megabase chromatin domains surrounding DSBs via poly-ADP-ribosylation, phosphorylation, acetylation, and protein assembly. The dynamics of these IR-induced foci (IRIF) have been implicated in DNA damage signaling and DNA repair. As an IRIF reporter, we tracked the relocalization of green fluorescent protein fused to a chromatin binding domain of the checkpoint adapter protein 53BP1 after IR of breast cancer cells and tumors. To block DSB repair in breast cancer cells and tumors, we targeted poly(ADP-ribose) polymerase (PARP) with ABT-888 (veliparib), one of several PARP inhibitors currently in clinical trials. PARP inhibition markedly enhanced IRIF persistence and increased breast cancer cell senescence both in vitro and in vivo, arguing for targeting IRIF resolution as a novel therapeutic strategy. Cancer Res; 70(15); 6277-82. ©2010 AACR.