Novel strategies to augment genetically delivered immunotoxin molecular therapy for cancer therapy.
Immunotoxin therapy is a promising molecular cancer treatment strategy. Its main advantage is seletive cytotoxicity towards tumor cells and minimal toxicity in normal tissues. However, a short half-life and rapid clearance severely hampers its clinical application. We report here a novel genetic approach in which a recombinant adenovirus vector was used to deliver an immunotoxin gene e23(scFv)-PE40 targeted to the oncogene c-erbB-2 (also known as Her2/neu). This vector, when combined with a low dose of a conditionally replicative adenovirus vector (CRAd), has enhanced tumor-killing ability either alone or in combination with the chemotherapeutic agent etoposide. Our data show that low-dose CRAd facilitated the replication of replication-deficient Ad-e23(scFv)-PE40 up to 6-20 times and the transcription of e23(scFv)-PE40 gene up to 12 times. Moreover, etoposide increased the e23(scFv)-PE40 transcription up to 8.5 times. Furthermore, we show that systemic application of Ad-e23(scFv)-PE40 and enhanced expression of the immunotoxin gene was well tolerated as determined by serum biochemical markers and histological examination of most vital organs. Taken together, our data support a novel genetic immunotoxin delivery approach that may yield enhanced efficacy against a variety of Her2/neu-expressing tumors.
Liu
X
X
Experimental Center, First People's Hospital, Shanghai Jiaotong University, Shanghai 200080, China.
Wu
J
J
Zhang
S
S
Li
C
C
Huang
Q
Q
D036002:ADP Ribose Transferases / Q000235:genetics / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000378:metabolism; D001427:Bacterial Toxins / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005098:Exotoxins / Q000235:genetics / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage*; D000922:Immunotoxins / Q000008:administration & dosage* / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000628:therapy*; D016133:Polymerase Chain Reaction; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D000911:Antibodies, Monoclonal; D001427:Bacterial Toxins; D005098:Exotoxins; D007155:Immunologic Factors; D000922:Immunotoxins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A