Synergistic anti-cancer effects of immunotoxin and cyclosporin in vitro and in vivo.
BACKGROUND
The clinical use of immunotoxins (ITs) has been hampered by hepatotoxicity, and the induction of a strong human-anti-IT response. The human-anti-IT response results in neutralisation of the immunoconjugates, rendering repetitive treatment inefficacious.


METHODS
We evaluated the combination of cyclosporin A (CsA) with various Pseudomonas exotoxin A-based ITs in human breast, cervical, and prostate cancer cell lines measured by protein synthesis, cell viability, and TUNEL assay. Furthermore, expression of essential proteins were analysed by western blot. We used cervical cancer model in nude rats to evaluate the anti-metastatic effect of the combination. The anti-immunogenic response by the CsA treatment was investigated in immunocompetent rats.


RESULTS
The combination of CsA with ITs caused remarkable synergistic cytotoxicity, in several cancer cell lines, characterised by protein synthesis inhibition, decreased cell viability, and an increased apoptotic index. Furthermore, the combination strongly inhibited formation of metastases in a cervical cancer model in nude rats with a statistically significant increase in median survival time of the combination-treated animals, as compared with those receiving a suboptimal dose of IT alone. Notably, we found in immunocompetent rats that the anti-IT immunoresponse elicited by repeated administration of IT was efficiently abrogated by CsA; notably the antibody responds towards the highly immunogenic PE was shown to be prevented.


CONCLUSIONS
The combination of ITs and CsA might constitute a significant improvement in the clinical potential of systemic IT treatment of cancer patients.
Andersson
Y
Y
Department of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Rikshospitalet University Hospital, Oslo N-0310, Norway. Yvonne.Andersson@rr-research.no
Engebraaten
O
O
Fodstad
Ø
Ø
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000008:administration & dosage*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage* / Q000276:immunology; D008297:Male; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental / Q000188:drug therapy; D051381:Rats; D020123:Sirolimus / Q000494:pharmacology; D016559:Tacrolimus / Q000494:pharmacology
D000970:Antineoplastic Agents; D000922:Immunotoxins; D016572:Cyclosporine; D020123:Sirolimus; D016559:Tacrolimus