Almost without exception, patients with localized tumors have better prognoses than patients with metastatic disease. The long-range goal of our studies is to develop safe, effective, systemic treatments for metastatic solid tumors. The basis of the approach described in this application is the use of neural progenitor cells (NPCs) to deliver cDNAs encoding therapeutic transgenes selectively to metastatic tumor loci. We propose to determine whether the tumor-tropic property of intravenously injected NPCs can be exploited to deliver the cDNA encoding a CPT-11-activating enzyme selectively to metastatic tumor sites. We will evaluate whether subsequent administration of CPT-11 to mice with metastatic neuroblastoma (NB) will eradicate micrometastatic disease. Preliminary and published data show that NPCs given by tail vein injection migrate to tumor loci regardless of the anatomic location of the tumors in mouse models. Preliminary data also show that NPCs transduced with replication-defective adenovirus encoding the CPT-11-activating enzyme rabbit carboxylesterase (rCE) express up to 1000-fold higher levels of CE activity than do human normal or tumor cells. The data support the hypothesis that intravenous administration of NPCs encoding rCE and CPT-11 may produce levels of SN-38 at tumor loci sufficient to eradicate residual disease, but minimize toxicity. Efficacy and toxicity studies will be done using esterase-deficient Es1e/SCID mice bearing disseminated NB. Preliminary Data show that NPCs migrate to metastatic NB tumors, and clinical trials indicate that CPT-11 has potential for the treatment of NB. This study is intended to show proof of principle specifically regarding the efficacy of NPC-directed enzyme prodrug therapy (NDEPT) with rCE and CPT-11 for NB. However, preclinical data document that NPCs also migrate to loci of several types of solid tumors such as glioblastoma and breast cancer. Therefore, the data generated may also provide proof of principle for the more general hypothesis that NPCs can be used as effective tumor-specific delivery vectors for therapeutic cDNAs. The described approach might then be adapted to the treatment of other solid tumors by careful choice of appropriate therapeutic transgenes.
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| Hatfield, Jason M; Wierdl, Monika; Wadkins, Randy M et al. (2008) Modifications of human carboxylesterase for improved prodrug activation. Expert Opin Drug Metab Toxicol 4:1153-65 |
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