TGF-ALPHA-PE40 INHIBITS NONSMALL CELL LUNG-CANCER GROWTH

The ability of a chimeric toxin containing transforming growth factor alpha (TGF alpha) and truncated Pseudomonas exotoxin A to inhibit NSCL C growth was investigated. TGF alpha-PE40 inhibited binding of I-125-E FT to NSCLC cell lines with an IC50 value of 0.5-3 mu g/ml. Similarly, other forms of the fusion protein, TGF alpha-PE38 and TGF alpha-PE40( Asp553), which have active TGF alpha binding domains, inhibited specif ic I-125-EGF binding to NSCLC cells with IC50 values of 0.1-2 and 0.05 -0.5 mu g/ml respectively. TGF alpha-PE40 inhibited S-35-methionine up take by NSCLC cells with an ED(50) value of 1-30 ng/ml. TGF alpha-PE38 , which has one of the two disulfide pairs of PE40, inhibited amino ac id uptake with ED(50) values of 3-50 ng/ml whereas TGF alpha-PE40(Asp5 53), which lacks ADP ribosylation activity, had an ED(50) > 100 ng/ml. TGF alpha-PE40 inhibited colony formation of NSCLC cells with an LD(5 0) values of 0.008-0.1 ng/ml. Similarly, TGF alpha-PE38 inhibited NSCL C colony formation with LD(50) values of 0.002-0.1 ng/ml whereas TGF a lpha-PE40(Asp553) had an LD(50) > 10 ng/ml. Also, TGF alpha-PE40 and T GF alpha-PE38 inhibited NSCLC xenograft formation in nude mice whereas TGF alpha-PE40(Asp553) was inactive. These data suggest that TGF alph a-PE40 and TGF alpha-PE38 may be useful agents to inactivate NSCLC cel ls.