Effect of Onconase ± Tamoxifen on ASPC-1 Human Pancreatic Tumors in Nude Mice

  • Intae Lee
  • Young H. Lee
  • Stanislaw M. Mikulski
  • Kuslima Shogen
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 530)


To evaluate changes in tumor physiological parameters after treatment with ONCONASE (ONC), we used laser Doppler flowmetery for tumor blood flow (TBF) in legs of nude mice bearing AsPC-1 human pancreatic carcinoma. Tumor interstitial fluid pressure (TIFP) was measured using the wick-inneedle technique, while intratumoral pO2 utilized O2 sensitive needle electrodes. TBF was significantly increased by an i.p. injection of ONC, then returned to the untreated levels at 150 min post-treatment. Single and multiple intraperitoneal injections of ONC significantly reduced TIFP (post-treatment at 1–7 days). ONC significantly improved tumor oxygenation evidenced by an increase in median pO2 from 4.2 mm Hg to 8.2 mm Hg. Since ONC had a synergistic interaction with tamoxifen (TAMX) on the cytotoxic clonogenicity of AsPC-1 tumor cells in vitro,we evaluated the antitumoral effects in vivo by ONC ± TAMX, using nude mice bearing AsPC-1 pancreatic tumor cells of ascite (intraperitoneally implanted) or solid (subcutaneously implanted to legs) tumors. ONC alone effectively retarded the tumor growth, but TAMX alone did not. ONC + TAMX was synergistically effective in inhibiting tumor growth.

Key words

ONCONASE tamoxifen tumor blood flow tumor interstitial fluid pressure intratumoral PO2 







tumor blood flow


tumor interstitial fluid pressure


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  1. 1.
    Jain RK. Barriers to drug delivery in solid tumors. Scientific Amer 1994;271:58–65.CrossRefGoogle Scholar
  2. 2.
    Lee I, Boucher Y, Jain RK. Nicotinamide can lower tumor interstitial hypertension: mechanistic and therapeutic implications. Cancer Res 1992;52:3237–3240.PubMedGoogle Scholar
  3. 3.
    Lee I, Demhartner TJ, Boucher Y, Jain RK, Intaglietta M. Effects of hemodilution and resuscitation on tumor interstitial fluid pressure, blood flow, and oxygenation. Microvasc Res 1994;48:1–12.PubMedCrossRefGoogle Scholar
  4. 4.
    Wu YN, Mikulski SM, Ardelt W, Rybak SM, Ypole RJ. A cytotoxic ribonuclease, study of the mechanism of onconase cytotoxicity. J Biol Chem 1993;268:10686–10693.PubMedGoogle Scholar
  5. 5.
    Lin JJ, Newton DL, Mikulski SM, Kung HF, Youle RJ, Rybak SM. Characterization of the mechanism of cellular and cell free protein synthesis inhibition by an anti-tumor ribonuclease. Biochem Biophysical Res Comm 1994;204:156–162.CrossRefGoogle Scholar
  6. 6.
    Mikulski SM, Viera A, Ardelt W, Menduke H, Shogen K. Tamoxifen and trifluoroperazine (Stelazine) potentiate cytostatic/ cytotoxic effects of P-30 protein, a novel protein possessing anti-tumor activity. Cell Tissue Kinet 1990;23:237–246.PubMedGoogle Scholar
  7. 7.
    Mikulski SM, Viera A, Shogen K. In vitro synergism between a novel amphibian oocytic ribonuclease (Onconase®) and tamoxifen, lovastatin and cisplatin, in human OVAR-3 ovarian carcinoma cell line. Int J Oncol 1992;1:779–785.PubMedGoogle Scholar
  8. 8.
    Leunig M, Goetz AE, Dellian M, Zetterer G, Gamarra F, Jain RK, Messmer K. Interstitial fluid pressure in solid tumors following hyperthermia: possible correlation with therapeutic response. Cancer Res 1992;52:487–490.PubMedGoogle Scholar
  9. 9.
    Vasandani VM, Wu Y, Mikulski SM, Youle RJ, Sung C. Molecular determinants in the plasma clearance and tissue distribution of ribonucleases of the ribonuclease A superfamily. Cancer Res 1996;56:4180–4186.PubMedGoogle Scholar
  10. 10.
    McClay EM, Winski PJ, Jones JA, Jennertte II J, Gattoni-Celli S. ∆12-prostaglandin-J2, is cytotoxic in human malignancies and synergizes with both cisplatin and radiation. Cancer Res 1996;56:3866–3869.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2003

Authors and Affiliations

  • Intae Lee
    • 1
    • 2
  • Young H. Lee
    • 2
  • Stanislaw M. Mikulski
    • 3
  • Kuslima Shogen
    • 3
  1. 1.Department of Radiation OncologyUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  2. 2.Division of Radiation ResearchUMDNJ-Robert Wood Johnson Medical SchoolCamdenUSA
  3. 3.Alfacell CorporationBloomfieldAustralia

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