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Possible Mechanisms Of Improved Radiation Response By Cytotoxic Rnase, Onconase®, On A549 Human Lung Cancer Xenografts Of Nude Mice

  • Dae Hong Kim
  • Eun Ju Kim
  • Anna Kalota
  • Alan M. Gewirtz
  • Jerry Glickson
  • Kuslima Shogen
  • Intae Lee
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 599)

Abstract

The cytotoxic RNase, Onconasemboxtextregistered (ONC), isolated from amphibian oocytes, was used to study its effect on the radiation response in A549 human NSCLC in vitro and in vivo. In cell culture studies, we found that ONC increased the radiation response by ONC-induced inhibition of O2 consumption (QO2). The occurrence of apoptosis was increased by ONC and was dependent on dosages and time exposure (measured by a Tunnel in situ cell death detection assay). Moreover, ONC inhibited sublethal damage repair (SLDR), confirmed by a split dose experiment. In animal studies, ONC significantly increased the radiation-induced tumor growth delay of A549 tumors in vivo. Using a non-invasive DCE-MRI technology, ONC-induced changes of perfusion were observed in A549 tumors. We concluded that the ONC-induced enhancement in tumor oxygenation was mainly due to the reduction in QO2 rather than an increase in tumor blood flow. This investigation suggests important potential clinical uses of ONC for the treatment of NSCLC cancer patients.

Keywords

Malignant Mesothelioma Radiation Response Tumor Blood Flow Tumor Oxygenation A549 Tumor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Mikulski S.M., Costanzi J.J., Vogelzang N.J., McCachren S., Taub R.N., Chun H., Mittelman A., Panella T., Puccio C., Fine R., and Shogen K., Phase II trial of a single weekly intravenous dose of ranpirnase in patients with unresectable malignant mesothelioma, J. Clin. Oncol. 20, 274-281 (2001).CrossRefGoogle Scholar
  2. 2.
    Rybak S.M. and Newton D.L., Natural and engineered cytotoxic ribonucleases: therapeutic potential, Experimental Cell Res. 253, 325-335 (1999).CrossRefGoogle Scholar
  3. 3.
    Iordanov M.S., Ryabinina O.P., Wong J., Dinh T.H., Newton D.L., Rybak S.M., and Magun B.E., Molecular determinants of apoptosis induced by the cytotoxic ribonuclease onconase: evidence for cytotoxic mechanisms different from inhibition of protein synthesis, Cancer Res. 60, 1983-1994 (2000).PubMedGoogle Scholar
  4. 4.
    Lee I., Lee Y.H., Mikulski S.M., Lee J., and .Shogen K., Enhanced cellular radiation sensitivity of androgen-independent human prostate tumor cells by onconase, Anticancer Res. 20, 1037-1040 (2000).PubMedGoogle Scholar
  5. 5.
    Lee I., Lee Y.H., Mikulski S.M., Lee J., Covone K., and Shogen K., Tumoricidal effects of onconase on various tumors, J. Surgical Oncology 73, 164-171 (2000).CrossRefGoogle Scholar
  6. 6.
    Tofts P.S. and Kermode A.G., Measurement of the blood-brain barrier permeability and leakage space using dynamic MR imaging. 1. Fundamental concepts, MRM 17, 357-367 (1991).Google Scholar
  7. 7.
    Tracy S., Mukohara T., Hansen M, Meyerson M., Johnson B.E., and Jaenne P.A., Gefitinib induces apoptosis in EFGRL858R non-small-cell lung cancer line H3255, Cancer Res. 64, 7241-7244 (2004).PubMedCrossRefGoogle Scholar
  8. 8.
    Lee I., Lee Y.H., Mikulski S.M., Shogen K., Effect of onconase ± tamoxifen on AsPC-1 human pancreatic tumors in nude mice, Adv. Exp. Med. Biol. 530, 187-196 (2003).PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Dae Hong Kim
    • 1
  • Eun Ju Kim
    • 1
  • Anna Kalota
    • 2
  • Alan M. Gewirtz
    • 2
  • Jerry Glickson
    • 1
  • Kuslima Shogen
    • 3
  • Intae Lee
    • 1
    • 4
  1. 1.Department of RadiologyUniversity of PennsylvaniaPhiladelphiaUSA
  2. 2.Department of Medicine (Division of Hematology/ Oncology)University of PennsylvaniaPhiladelphiaUSA
  3. 3.Alfacell CorporationBloomfieldUSA
  4. 4.Department of RadiologyUniversity of Pennsylvania, B6 Blockley Hall, 423 Guardian DrivePhiladelphiaUSA

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