Abstract
Purpose
The effect of multiple small dosages of the cytotoxic RNase, ranpirnase (ONCONASE®, ONC), on lung cancer was studied. The possible mechanisms for the enhanced tumoricidal efficacy of multiple small dosages of ONC were also investigated.
Methods
Hematoxylin and eosin staining, TUNEL labeling, and caspase-3-antibody labeling were used for in vivo analysis of apoptosis. A growth-delay assay was applied to detect the therapeutic potential of small and multiple dosages of ONC in vivo. ONC-induced changes in blood flow in A549 tumors and the kidney were measured non-invasively by dynamic contrast enhanced magnetic resonance imaging (DCE-MRI).
Results
In cell culture studies, ONC significantly inhibited tumor growth of A549 human NSCLC cells without damaging non-cancerous cells (HLF-1 human lung fibroblast). Multiple small dosages of ONC significantly prolonged tumor growth delay of A549 tumors, with increased apoptosis in vivo from 0.5 ± 0.3 to 70.1 ± 1.1% (by TUNEL labeling, N = 3, P < 0.05). Interestingly, multiple small doses of ONC were more effective than a single large dose for the inhibition of tumor growth with reduced side effect. Using non-invasive DCE-MRI methods, we found that the mean of the K trans median values increased to 49.3 ± 7.5% from the pre-ONC values by ONC (N = 4 mice, P < 0.05). A subsequent T 1 map of the kidney showed that T 1 values were temporarily decreased for up to 2 days (however, fully recovered ∼4 days post-treatment).
Conclusions
Multiple small dosages of ONC significantly inhibited tumor growth of A549 NSCLC cells in vivo, with markedly increased apoptosis. This investigation suggests important potential clinical uses of ONC for the treatment of NSCLC cancer patients.
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Acknowledgments
This research was supported by Alfacell Corporation through their sponsorship research agreement with the University of Pennsylvania. The authors would like to express their thanks to Dr. Dae H. Kim’s assistance on the MRI studies. The authors also appreciate Daniel Martinez at the Pathology Core, Children’s Hospital of Philadelphia (CHOP), for his histological services for processing paraffin blocks and slides for the H & E staining, caspase-3 antibody labeling, and TUNEL staining studies.
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Lee, I., Shogen, K. Mechanisms of enhanced tumoricidal efficacy of multiple small dosages of ranpirnase, the novel cytotoxic ribonuclease, on lung cancer. Cancer Chemother Pharmacol 62, 337–346 (2008). https://doi.org/10.1007/s00280-007-0637-y
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DOI: https://doi.org/10.1007/s00280-007-0637-y