Mechanisms of enhanced tumoricidal efficacy of multiple small dosages of ranpirnase, the novel cytotoxic ribonuclease, on lung cancer
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- Lee, I. & Shogen, K. Cancer Chemother Pharmacol (2008) 62: 337. doi:10.1007/s00280-007-0637-y
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.
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).
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 Ktrans median values increased to 49.3 ± 7.5% from the pre-ONC values by ONC (N = 4 mice, P < 0.05). A subsequent T1 map of the kidney showed that T1 values were temporarily decreased for up to 2 days (however, fully recovered ∼4 days post-treatment).
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.