Inhibition of PARP-1 by Olaparib (AZD2281) Increases the Radiosensitivity of a Lung Tumor Xenograft

Abstract

PARP-1 is a critical enzyme in the repair of DNA strand breaks. Inhibition of PARP-1 increases the effectiveness of radiation in killing tumor cells. However, although the mechanism(s) are well understood for these radiosensitizing effects in vitro, the underlying mechanism(s) in vivo are less clear. Nicotinamide, a drug structurally related to the first generation PARP-1 inhibitor, 3-aminobenzamide, reduces tumor hypoxia by preventing transient cessations in tumor blood flow, thus improving tumor oxygenation and sensitivity to radiotherapy. Here, we investigate whether olaparib, a potent PARP-1 inhibitor, enhances radiotherapy, not only by inhibiting DNA repair but also by changing tumor vascular hemodynamics in non-small cell lung carcinoma (NSCLC). In irradiated Calu-6 and A549 cells, olaparib enhanced the cytotoxic effects of radiation (sensitizer enhancement ratio at 10% survival ¼ 1.5 and 1.3) and DNA double-strand breaks persisted for at least 24 hours after treatment. Combination treatment of Calu-6 xenografts with olaparib and fractionated radiotherapy caused significant tumor regression (P ¼ 0.007) relative to radiotherapy alone. To determine whether this radiosensitization was solely due to effects on DNA repair, we used a dorsal window chamber model to establish the drug/radiation effects on vessel dynamics. Olaparib alone, when given as single or multiple daily doses, or in combination with fractionated radiotherapy, increased the perfusion of tumor blood vessels. Furthermore, an ex vivo assay in phenylephrine preconstricted arteries confirmed olaparib to have higher vasodilatory properties than nicotinamide. This study suggests that olaparib warrants consideration for further development in combination with radiotherapy in clinical oncology settings such as NSCLC. Mol Cancer Ther; 10(10); 1949-58. Ó2011 AACR.

PET of Poly (ADP-Ribose) Polymerase Activity in Cancer: Preclinical Assessment and First In-Human Studies

“…PARP1, the best-understood member of this family, facilitates base excision repair (2) and mediates important alternative DNA repair pathways (3). Preclinical studies identified PARP-mediated DNA repair as an essential survival mechanism for breast and ovarian cancers harboring BRCA1 or BRCA2 mutations deleterious to the homologous recombination DNA repair pathway (4,5). Thus, PARP inhibition in these cancers results in massive genomic instability that leads to cell death by synthetic lethality (6,7).…”

Therapeutic targeting of constitutive PARP activation compromises stem cell phenotype and survival of glioblastoma-initiating cells

“…[21][22][23][24][25][26][27] In vivo, PARP inhibitors enhance radiation therapy in syngeneic and xenograft models for colon, lung, head and neck, and cervical cancers. 21,[28][29][30][31][32] Olaparib (AZD2281), which targets PARP1 and PARP2, is currently in several phase I and phase II trials for solid tumors as a single agent or in combination with chemotherapy and/or radiotherapy. 33 A phase I study is ongoing for olaparib plus temozolomide in patients with relapsed GBM (http://www.…”

Radiosensitisation by Poly(ADP-ribose) Polymerase Inhibition

“…Immunohistochemical analysis of tumour sections after combined treatment revealed an increased number of apoptotic cells and a decrease in proliferating cells [84,87]. As previously described for nicotinamide and other benzamide analogs [92], PARP inhibitors can induce temporary vasodilation increasing perfusion of tumour blood vessels [82,85]. This vascular side effect of PARP inhibitors treatment enhances drug delivery (e.g.…”

“…A number of PARP inhibitors (ABT-888/Veliparib, AZD-2281/Olaparib, AG014699/ Rucaparib, MK-4827/Niraparib, AG14361, GPI-15427, E7016) have been shown to enhance tumour sensitivity to radiation in syngeneic and xenograft models of breast [79,80], colon [81][82][83], lung [79,84,85], nasopharyngeal [86], head and neck [87], and brain tumours [88][89][90][91] (Table 11.1). PARP inhibition combined with Colon carcinoma (SW620, LoVo) AG14361, i.p., 30 min before X-rays (5 or ionising radiation resulted in delayed tumour growth and extended median survival time.…”