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The Therapeutic Mechanisms of Enhancement of Radiation Response on Lung Cancer by Ranpirnase
Proceedings of the 49th Annual ASTRO Meeting hypothesis that replication-competent adenovirus-mediated suicide gene therapy when combined with intensity modulated radiation therapy (IMRT) will improve outcome over IMRT alone in newly-diagnosed, intermediate-risk prostate cancer.
Author Disclosure: B. Movsas, None; H. Stricker, None; K. Barton, None; S. Brown, None; J. Peabody, None; M. Lu, None; M. Elshaikh, None; J.H. Kim, patent pending, E. Ownership Interest; S.O. Freytag, patent pending, E. Ownership Interest.
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The Therapeutic Mechanisms of Enhancement of Radiation Response on Lung Cancer by Ranpirnase
I. Lee1, D. Martinez2, S. Magnitsky1, D. H. Kim1, U. Sunar1, B. R. Pawel2, K. Shogen3 1 University of Pennsylvania, Philadelphia, PA, 2Children’s Hospital of Philadelphia, Philadelphia, PA, 3Alfacell Corporation, Bloomfield, NJ Purpose/Objective(s): We investigated the therapeutic potential of the combination of radiation therapy and cytotoxic RNase, ranpirnase (ONCONASEÒ: ONC), in human lung tumor models. We used non-invasive monitoring methods to examine the underlying mechanisms of ONC. Materials/Methods: H & E staining, TUNEL staining, and caspase-3-antibody labeling were used for in vivo analysis of apoptosis. Growth-delay assay was applied to detect the therapeutic potential of ONC as a radiation sensitizer in vivo. ONC-induced changes in blood flow and biochemical metabolites were measured non-invasively by dynamic contrast enhanced (DCE) MRI, non-localized 1H MRS (acquired using a SelMQC pulse sequence), and near-infrared spectroscopy-NIRS (diffuse correlation spectroscopy and diffuse reflectance spectroscopy) methods. Results: In cell culture studies, ONC significantly inhibited tumor growth of A549 & NCI-H1975 human NSCLC and MDA-MB-231 & MCF-7 human breast cancer cells without damaging non-cancerous cells (HLF-1 human lung fibroblast and NCI/3T3 fibroblast). ONC significantly increased the radiation-induced tumor growth delay of A549 tumors, with remarkable increases in apoptosis in vivo. It was observed, when using a DCE MRI method, that the mean of the Ktrans median values from 4 tumors for the pre-ONC was 0.0812 ± 0.014 and that of post-ONC was 0.1237 ± 0.0279, resulting in a 49.3 ± 7.5% increase (N = 4 mice, p\0.05). The increases in the Ktrans value of tumor regions are shown in red, and are mainly due to significant increases at the rim of the tumor regions at 1.5 h post-injection (7 slices/tumor; 1st–4th row in Figure). A 20% decrease (n = 3 mice, p \ .05) in lactate was observed using non-localized MRS (5th row in Figure). To confirm the MRI blood flow data, relative blood flow (rBF) and blood oxygen levels (SO2) were non-invasively monitored by a near-infrared spectroscopy-NIRS method in A549 tumors and skeletal muscles before and after treatment with ONC or saline. The rBF in A549 tumors was not altered by saline alone, compared to ONC. In the ONC-treated group, the rBF in A549 tumors at 1.5 h increased by 70% (n = 8 mice, p\.05) but remained unchanged in skeletal muscles. The SO2 in A549 tumors significantly increased from 14 ± 4% to 32 ± 3% (n = 8 mice, p \ .05), but not in skeletal muscles. Conclusions: ONC significantly increased the radiation-induced tumor growth delay of lung tumors in vivo and improved several physiological parameters with minimal side effects. ONC may be a new and promising drug for the treatment of NSCLC as a radiation therapy enhancer.
Author Disclosure: I. Lee, None; D. Martinez, None; S. Magnitsky, None; D.H. Kim, None; U. Sunar, None; B.R. Pawel, None; K. Shogen, CEO and President of Alfacell Coprporation, A. Employment.
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Author Disclosure: B. Movsas, None; H. Stricker, None; K. Barton, None; S. Brown, None; J. Peabody, None; M. Lu, None; M. Elshaikh, None; J.H. Kim, patent pending, E. Ownership Interest; S.O. Freytag, patent pending, E. Ownership Interest.
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The Therapeutic Mechanisms of Enhancement of Radiation Response on Lung Cancer by Ranpirnase
I. Lee1, D. Martinez2, S. Magnitsky1, D. H. Kim1, U. Sunar1, B. R. Pawel2, K. Shogen3 1 University of Pennsylvania, Philadelphia, PA, 2Children’s Hospital of Philadelphia, Philadelphia, PA, 3Alfacell Corporation, Bloomfield, NJ Purpose/Objective(s): We investigated the therapeutic potential of the combination of radiation therapy and cytotoxic RNase, ranpirnase (ONCONASEÒ: ONC), in human lung tumor models. We used non-invasive monitoring methods to examine the underlying mechanisms of ONC. Materials/Methods: H & E staining, TUNEL staining, and caspase-3-antibody labeling were used for in vivo analysis of apoptosis. Growth-delay assay was applied to detect the therapeutic potential of ONC as a radiation sensitizer in vivo. ONC-induced changes in blood flow and biochemical metabolites were measured non-invasively by dynamic contrast enhanced (DCE) MRI, non-localized 1H MRS (acquired using a SelMQC pulse sequence), and near-infrared spectroscopy-NIRS (diffuse correlation spectroscopy and diffuse reflectance spectroscopy) methods. Results: In cell culture studies, ONC significantly inhibited tumor growth of A549 & NCI-H1975 human NSCLC and MDA-MB-231 & MCF-7 human breast cancer cells without damaging non-cancerous cells (HLF-1 human lung fibroblast and NCI/3T3 fibroblast). ONC significantly increased the radiation-induced tumor growth delay of A549 tumors, with remarkable increases in apoptosis in vivo. It was observed, when using a DCE MRI method, that the mean of the Ktrans median values from 4 tumors for the pre-ONC was 0.0812 ± 0.014 and that of post-ONC was 0.1237 ± 0.0279, resulting in a 49.3 ± 7.5% increase (N = 4 mice, p\0.05). The increases in the Ktrans value of tumor regions are shown in red, and are mainly due to significant increases at the rim of the tumor regions at 1.5 h post-injection (7 slices/tumor; 1st–4th row in Figure). A 20% decrease (n = 3 mice, p \ .05) in lactate was observed using non-localized MRS (5th row in Figure). To confirm the MRI blood flow data, relative blood flow (rBF) and blood oxygen levels (SO2) were non-invasively monitored by a near-infrared spectroscopy-NIRS method in A549 tumors and skeletal muscles before and after treatment with ONC or saline. The rBF in A549 tumors was not altered by saline alone, compared to ONC. In the ONC-treated group, the rBF in A549 tumors at 1.5 h increased by 70% (n = 8 mice, p\.05) but remained unchanged in skeletal muscles. The SO2 in A549 tumors significantly increased from 14 ± 4% to 32 ± 3% (n = 8 mice, p \ .05), but not in skeletal muscles. Conclusions: ONC significantly increased the radiation-induced tumor growth delay of lung tumors in vivo and improved several physiological parameters with minimal side effects. ONC may be a new and promising drug for the treatment of NSCLC as a radiation therapy enhancer.
Author Disclosure: I. Lee, None; D. Martinez, None; S. Magnitsky, None; D.H. Kim, None; U. Sunar, None; B.R. Pawel, None; K. Shogen, CEO and President of Alfacell Coprporation, A. Employment.
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