Gene Therapy with SLPI Promoter Controlled Replication-competent Adenovirus for Non-small Cell Lung Cancer

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Secretory leukoprotease inhibitor (SLPI) is highly expressed in almost all non-small cell lung cancers (NSCLC), but not in the majority of other tumor types. In an attempt to create a specific gene therapy for NSCLC, we constructed AdSLPIE1AdB, an adenovirus vector with a double expression cassette consisting of E1A driven by the SLPI promoter gene followed by E1B-19K under the control of the CMV promoter that can selectively replicate only in NSCLC cells. Infection of AdSLPI.E1AdB yielded E1A protein expression and adenovirus replication resulting in a more than 100 fold increase of the virus titers only in SLPI-producing NSCLC cells (A549, H358, and HS24). In contrast, neither E1A protein nor replication was detected in non SLPI-producing HepG2 cells. Treatment with AdSLPI.EIAdB significantly inhibited the proliferation of NSCLC cells in vitro in a dose dependent manner, whereas the cell growth of HepG2 or normal human bronchial epithelial cells was not affected by AdSLPI.E1AdB infection. Direct injection of AdSLPI.E1AdB into A549 and H358 tumors in nude mice resulted in a marked reduction in tumor growth compared to controls (A549: 57%, p<0.02, H358: 67%, p<0.03). Histological examination revealed the replication of AdSLPI.E1AdB and strong induction of necrosis and apoptosis. In addition, we evaluated the combination of AdSLPI.E1AdB and AdCMVNK4 encoding NK4 protein which has strong anti-angiogenic activity E1A expressed by AdSLPI.E1AdB trans-acts on the replication of AdCMVNK4 and thus increases the expression of NK4. Injection of these two vectors into H358 tumors resulted i n a more striking reduction of tumor growth compare to single injection of each vector. These results suggest that AdSLPI.E1AdB could provide a selective therapeutic modality for NSCLC and that the combination of AdSLPI.E1AdB and AdCMVNK4 maybe a more effective gene therapy for NSCLC.