Antitumor efficacy of the cytotoxic RNase, ranpirnase, on A549 human lung cancer xenografts of nude mice.
BACKGROUND
The cytotoxic RNase, ranpirnase (ONCONASE, ONC), may have promising therapeutic implication as an alternative for cisplatin for the treatment of lung cancer, due to inhibition of protein synthesis by t-RNA cleavage.


METHODS
A549 and NCI-H1975 human NSCLC cell lines were cultured in the presence and absence of ONC. Cytotoxicity was monitored using a clonogenic assay. Using an inverted phase and fluorescence microscope, we studied whether apoptosis was induced by ONC in gefitinib-induced apoptosis-resistant A549 tumor cells. The therapeutic effectiveness of ONC was studied via single and multiple administrations on A549 human non-small cell lung cancer (NSCLC), including tumors previously untreatable by cisplatin. ONC-induced changes in ATP levels were also monitored by non-localized phosphorus MR spectroscopy.


RESULTS
ONC significantly inhibited the cell growth of A549 tumors. Apoptosis was significantly induced by ONC in a dose-dependent manner. In animal studies, multiple small doses of ONC were more effective than one large single dose for the inhibition of tumor growth with reduced side-effects, probably due to the normalization of leaky tumor vessels. ONC in combination with cisplatin significantly reduced tumor growth of A549 tumors. In large tumors, including those unsuccessfully treated with cisplatin, ONC showed inhibition of tumor growth, while a second treatment of cisplatin did not. During monitoring by non-localized phosphorus MR spectroscopy, ATP levels decreased, likely due to ONC-induced inhibition of oxygen consumption (QO2).


CONCLUSIONS
ONC significantly inhibited tumor growth of A549 NSCLC cells in both in vitro and in vivo studies. This investigation suggests important potential clinical uses of ONC for the treatment of NSCLC cancer patients.
Lee
Intae
I
Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104-6069, USA. leeint@uphs.upenn.edu
Kalota
Anna
A
Gewirtz
Alan M
AM
Shogen
Kuslima
K
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D012260:Ribonucleases / Q000008:administration & dosage / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D000255:Adenosine Triphosphate; D012260:Ribonucleases; D002945:Cisplatin; C058703:ranpirnase