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Nucl Med Commun. 2011 Nov;32(11):1046-51. doi: 10.1097/MNM.0b013e32834a369b.

Poly(ADP-ribose) polymerase inhibitors combined with external beam and radioimmunotherapy to treat aggressive lymphoma.

Author information

1
Division of Nuclear Medicine, Russell H. Morgan Department of Radiology and Radiological Sciences, Sidney Kimmell Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-0817, USA.

Abstract

PURPOSE:

To assess the possible radiosensitizing capabilities of two different poly(ADP-ribose) polymerase (PARP) inhibitors in combination with external beam and I-tositumomab in a non-Hodgkin's lymphoma cell line.

METHODS AND MATERIALS:

Epstein-Barr virus-infected human Raji lymphoma cells with lentivirally transfected green fluorescent protein and luciferase in log-phase growth were incubated with various doses of AZD-2281 and ABT-888 24 h before external beam radiation exposure. A 500 nmol/l concentration of AZD-2281 and ABT-888 was used to assess the growth curve of Raji lymphoma cells over 5 days. The number of double-stranded breaks was visually assessed using a H2AX antibody and confocal microscopy. Intracellular PARP activity was measured 2 h after incubation with AZD-2281 (500 nmol/l) and ABT-888 using a colorimetric PARP assay kit. The radiosensitizing effect of AZD-2281 (500 nmol/l) with various doses of I-tositumomab was assessed after 24 h.

RESULTS:

A volume of 500 nmol/l of AZD-2281 and 500 nmol/l of ABT-888, in combination with 0, 4, 8, and 12 Gy external beam radiation, showed a 5.2, 7.1, 10.1, and 33.1% radiosensitization. A measure of 500 nmol/l AZD-2281 and ABT-888 significantly reduced the percentage of viable cells on days 3-5 compared with controls. The maximal relative reduction in viable cells was 78.5%, and this occurred with AZD-2281 (500 nmol/l) on day 5. AZD-2281 revealed a higher number of double-stranded breaks with confocal microscopy than did ABT-888. Two hours after incubation of Raji cells with 500 nmol/l of AZD-2281 or ABT-888, the colorimetric PARP activity assay showed a reduction of 30.36% with ABT-888 and of 47.8% with AZD-2281. Combining AZD-2281 (500 nmol/l) with 0, 5 μCi (0.185 MBq), 10 μCi (0.37 MBq) and 20 μCi (0.74 MBq) ¹³¹I-tositumomab revealed a significant reduction in cell viability after 24 h with 5 μCi (0.185 MBq) (P<0.01) and 10 μCi (0.37 MBq) (P<0.01) radiation dose.

CONCLUSION:

PARP inhibitors AZD-2281 and ABT-888 are highly radiosensitizing agents when used before external beam radiation and ¹³¹I-tositumomab.

PMID:
21956491
PMCID:
PMC4337870
DOI:
10.1097/MNM.0b013e32834a369b
[Indexed for MEDLINE]
Free PMC Article

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