Toxin-Based Therapeutic Approaches

Shapira, Assaf; Benhar, Itai

In another study, expression of DT-A in subcutaneous injected syngeneic bladder tumor cell lines in mice was driven by the previously described H19 gene regulatory sequence (which is expressed in tumors derived from tissues (such as bladder) that exhibited the gene during embryonic development [404] ). Intratumoral injection of the DNA vector as a calcium phosphate precipitate caused a significant suppression of subcutaneous tumor growth, with no obvious toxicity toward the host [405] . Significant suppression of tumor growth in animals and nearly complete ablation of the tumor in two human patients was also reported by the same group following intravesicle (into the bladder) administration of the DTA-H19 vector (which also showed high killing potential in ovarian cancer cells, see above) complexed with the transfection enhancer reagent Jet-PEI. No apparent toxicity toward the host was observed [406] . Phase I/II clinical studies in 18 patients with H19 over expressing superficial bladder cancer showed 22% complete response and 44% complete marker tumor ablation or a 50% reduction of the marker lesion after six treatments in which the DTA-H19 (BC-819) vector was administrated intravesically as a complex with polyethyleneimine. No dose limiting toxicity was observed and the most frequent adverse events were mild to moderate bladder discomfort, dysuria, micturition urgency, urinary tract infection, diarrhea, hypertension and asthenia [344] .