Selective activity of BS-RNase against anaplastic thyroid cancer.
BACKGROUND
Anaplastic thyroid carcinoma is an aggressive solid tumor that fails to adequately respond to any known chemotherapeutic regimen. The development of effective chemotherapy agents would provide the best chance for long-term survival of patients.


METHODS
The cytotoxic effects of bovine seminal ribonuclease (BS-RNase) against thyroid carcinoma cell lines with different degrees of differentiation in comparison to non-malignant cells, including human foreskin fibroblasts (HFF) and retinal pigment epithelial cells (RPE), were tested using the MTT dye reduction assay. Induction of apoptosis was demonstrated by annexin V assay and expression of proteins related to apoptosis was investigated by flow cytometry. The antitumoral in vivo effects of BS-RNase were assessed on established xenografts of anaplastic thyroid carcinoma cell line 8505C in nude mice using subcutaneous injections of BS-RNase (12.5 mg/kg once a day, on 20 consecutive days).


RESULTS
All the tumor cell lines exhibited marked sensitivity against BS-RNase in comparison to HFF and RPE cells. The greatest growth inhibition was seen in the 8505C line, while IC50 values for papillary (B-CPAP) and poorly-differentiated thyroid carcinoma cells were about 6-fold higher. The cytotoxic action of BS-RNase was associated with induction of apoptosis. Expressions of Fas and Fas-ligand were not influenced by BS-RNase completely, while the down-regulation of Bcl-2 in treated cells was observed. In vivo treatment induced significant tumor regression after the course of 20 consecutive days. No apparent toxic effects of BS-RNase toward non-malignant cells were observed during the in vivo treatment. After cessation of therapy (day 20) tumor volume continued to decrease and the tumor was no longer detectable after 30 days of treatment induction in all animals.


CONCLUSIONS
BS-RNase may have beneficial effects for treatment of aggressive anaplastic thyroid cancer.
Kotchetkov
R
R
Pediatric Clinic for Hematology and Oncology, University Clinics, Johann Wolfgang Goethe-University, Paul-Ehrlich Str. 40, D-60596 Frankfurt am Main, Germany.
Cinatl
J
J
Krivtchik
A A
AA
Vogel
J U
JU
Matousek
J
J
Pouckova
P
P
Kornhuber
B
B
Schwabe
D
D
Cinatl
J
J
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis; D002417:Cattle; D004722:Endoribonucleases / Q000494:pharmacology / Q000627:therapeutic use*; D053222:Fas Ligand Protein; D005260:Female; D006801:Humans; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000096:biosynthesis
D000970:Antineoplastic Agents; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D019014:fas Receptor; D004722:Endoribonucleases; C032523:ribonuclease SPL