The combination of chemotherapy with HVJ-E containing Rad51 siRNA elicited diverse anti-tumor effects and synergistically suppressed melanoma.

Abstract

Dacarbazine (DTIC) is one of the most popular alkylating agents used for the treatment of malignant melanoma. DTIC induces apoptosis of melanoma cells via double-strand breaks (DSBs). Melanoma cells, however, tend to increase their expression of DNA repair molecules in order to be resistant to DTIC. Here, we show that DTIC increases expression of Rad51, but not Ku70, in a cultured B16-F10 mouse melanoma cell line in dose- and time-dependent manners. On introducing Rad51 short interfering RNA (siRNA) with the hemagglutinating virus of Japan envelope (HVJ-E) to B16-F10 cells, DSBs induced by DTIC treatment were not efficiently repaired and resulted in enhanced apoptotic cell death. Colony formation of B16-F10 cells that received Rad51 siRNA was significantly decreased by DTIC treatment as compared with cells that received scramble siRNA. In melanoma-bearing mice, the combination of three intratumoral injections of HVJ-E containing Rad51 siRNA and five intraperitoneal injections of DTIC at a clinical dose synergistically suppressed the tumors. Moreover, HVJ-E demonstrated anti-tumor immunity by inducing cytotoxic T lymphocytes to B16-F10 cells on administration of DTIC. These results suggest that the combination of chemotherapy with HVJ-E containing therapeutic molecules will provide a promising therapeutic strategy for patients bearing malignant tumors resistant to chemotherapeutic agents.

• Authors: E Kiyohara, K Tamai, I Katayama, Y Kaneda
• Journal: Gene therapy (Gene Ther) Vol. 19 Issue 7 Pg. 734-41 (Jul 2012) ISSN: 1476-5462 [Electronic] England
• PMID: 21900962 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Nuclear
• Antineoplastic Agents, Alkylating
• DNA-Binding Proteins
• RNA, Small Interfering
• Dacarbazine
• Rad51 Recombinase
• Rad51 protein, mouse
• Xrcc6 protein, mouse
• Ku Autoantigen

Topics

• Animals
• Antigens, Nuclear (metabolism)
• Antineoplastic Agents, Alkylating (administration & dosage)
• DNA Breaks, Double-Stranded
• DNA Repair (drug effects)
• DNA-Binding Proteins (metabolism)
• Dacarbazine (administration & dosage)
• Female
• Ku Autoantigen
• Melanoma, Experimental (drug therapy, genetics, therapy)
• Mice
• Mice, Inbred C57BL
• RNA, Small Interfering (pharmacology)
• Rad51 Recombinase (genetics, metabolism)
• Sendai virus (genetics)
• Skin Neoplasms (drug therapy, genetics, therapy)