Author of

• 17783

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  P2.05 - Poster Session with Presenters Present (ID 463)

  • Event: WCLC 2016
  • Type: Poster Presenters Present
  • Track: Radiotherapy
  • Presentations: 1
  • Moderators:
  • Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)

  • 17787

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    P2.05-004 - ABT-737, a BH3 Mimetic, Enhances Therapeutic Effect of Ionizing Radiation in Murine Lung Cancer Model (ID 5895)

    14:30 - 14:30  |  Author(s): J.M. Lee
    • Abstract

    Background:
    Radiotherapy is one of the main treatment modalities of lung cancer, but its effectiveness is often hampered because of dose dependent radiation toxicity. Aberration of apoptotic pathway after irradiation is another mechanism attenuating therapeutic effect of radiation. ABT-737, a ‘first-in-class’ of BH3 mimetics, disrupts the BCL-2/BAK complex and initiates BAK-dependent intrinsic apoptotic pathway. In this study, we sought that ABT-737 is able to maximize the therapeutic effects of radiation in experimental animal models.
    
    Methods:
    Kras:p53[fl/fl] double mutant mice were obtained by genotyping of offspring from LSL Kras G12D and p53[fl/fl ]mouse. Lung cancer was induced by inhalation of 5 X 10[7] PFU AdCre viral particles at 8 weeks age. After 12 (± 2) weeks of inhalation, the mice were randomized and treated with either vehicle or ABT-737 (50 mg/kg, i.p., daily) for 3 days. Then mice underwent microCT and were irradiated in the left lung at a dose of 20 Gy using X-rad 320. In 2 weeks, 2[nd] round microCT was performed and lungs were harvested for histological analysis.
    
    Results:
    When the changes in the expression of pro-apoptotic and anti-apoptotic molecules after 20 Gy of irradiation were evaluated by immunoblotting, the decrease of BCL2-like 11 (BCL2L11) was most prominent in the irradiated lung. The tumor area was decreased in the irradiated lung of both vehicle and ABT-737 pretreated mice and inhibitory effect was remarkable when the mice were pretreated with ABT-737. Disputed tumor structure with apoptotic bodies were most frequently observed in the irradiated lung of ABT-737 pretreated mice. To quantify the apoptotic effect of this combination, immunohistochemical analysis against activated caspase-3 was performed. Counts of activated caspase-3 were significantly higher in the irradiated lung with ABT-737 pretreatment, suggesting ABT-737 possesses radiosensitizing property.
    
    Conclusion:
    Decrease of BCL2L11 expression in the irradiated lung is one of prominent findings, which might compromise therapeutic effect of radiation. Pretreatment of ABT-737 enhanced anti-tumor effect of ionizing radiation in Kras:p53[fl/fl] lung cancer model, suggesting BH3 mimetics would be a good candidate of radiosensitizer in lung cancer. Further studies are warranted for identification of optimal dosing and schedule of this combination treatment.