Canstatin gene electrotransfer combined with radiotherapy: preclinical trials for cancer treatment.
Given as a prophylactic treatment, a single muscle electrogene transfer of plasmid coding canstatin fused to human serum albumin (CanHSA), slowed down the development of two xenografted human carcinomas from mammary (MDA-MB-231) and prostate origin (PC-3) in nude mice and delayed lung metastatic spreading of B16F10 melanoma cells in syngenic mice. No effect was observed with unfused canstatin. The long lasting circulating blood level of CanHSA (20 ng ml(-1)) resulted in a profound disorganization of the tumor blood vessel network. However, when used as a curative treatment, on well-established tumors, CanHSA electrogenetherapy was ineffective in reducing tumor growth. As radiation is known to increase the alpha v beta3 and alpha v beta5 integrins, which are canstatin receptors, to extend the use of CanHSA electrogenetherapy, as a curative treatment, we explored the combination of CanHSA and ionizing radiation. We demonstrated a better efficacy (P=0.01) of the bitherapy over irradiation alone, as a result of strong vessel disorganization and dramatic increase of tumor cells apoptosis. This extremely simple virus free curative protocol could open the door to potential clinical applications, especially for prostate cancer that often develops radioresistance.
Magnon
C
C
CNRS, UMR8121, Vectorologie et Transfert de Gènes, Villejuif, Cedex, France.
Opolon
P
P
Connault
E
E
Mir
L M
LM
Perricaudet
M
M
Martel-Renoir
D
D
D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000532:radiotherapy / Q000628:therapy*; D045744:Cell Line, Tumor; D024141:Collagen Type IV / Q000097:blood / Q000235:genetics*; D003131:Combined Modality Therapy; D018274:Electroporation; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D018482:Muscle, Skeletal / Q000378:metabolism; D010446:Peptide Fragments / Q000097:blood / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000532:radiotherapy / Q000628:therapy*; D011879:Radiotherapy Dosage; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000627:therapeutic use*; D012709:Serum Albumin / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
C502625:COL4A2 protein, human; D024141:Collagen Type IV; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D012709:Serum Albumin