Tumor-Targeted Enzyme/Prodrug Therapy Mediates Long-term Disease-Free Survival of Mice Bearing Disseminated Neuroblastoma

St. Jude Children's Research Hospital, Memphis, Tennessee, United States
Cancer Research (Impact Factor: 9.33). 02/2007; 67(1):22-5. DOI: 10.1158/0008-5472.CAN-06-3607
Source: PubMed


Neural stem cells and progenitor cells migrate selectively to tumor loci in vivo. We exploited the tumor-tropic properties of HB1.F3.C1 cells, an immortalized cell line derived from human fetal telencephalon, to deliver the cDNA encoding a secreted form of rabbit carboxylesterase (rCE) to disseminated neuroblastoma tumors in mice. This enzyme activates the prodrug CPT-11 more efficiently than do human enzymes. Mice bearing multiple tumors were treated with rCE-expressing HB1.F3.C1 cells and schedules of administration of CPT-11 that produced levels of active drug (SN-38) tolerated by patients. Both HB1.F3.C1 cells and CPT-11 were given i.v. None of the untreated mice and 30% of mice that received only CPT-11 survived long term. In contrast, 90% of mice treated with rCE-expressing HB1.F3.C1 cells and 15 mg/kg CPT-11 survived for 1 year without detectable tumors. Plasma carboxylesterase activity and SN-38 levels in mice receiving both rCE-expressing HB1.F3.C1 cells (HB1.F3.C1/AdCMVrCE) and CPT-11 were comparable with those in mice receiving CPT-11 only. These data support the hypothesis that the antitumor effect of the described neural stem/progenitor cell-directed enzyme prodrug therapy (NDEPT) is mediated by production of high concentrations of active drug selectively at tumor sites, thereby maximizing the antitumor effect of CPT-11. NDEPT approaches merit further investigation as effective, targeted therapy for metastatic tumors. We propose that the described approach may have greatest use for eradicating minimum residual disease.

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Available from: Philip M Potter
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    • "indicates that MSCs are prominent for drug delivery in cancers, including ovarian, prostate, head and neck as well as hematological malignancies. MSCs can be expressed to deliver cytokines, prodrugs, apoptosis inducing proteins, and anti-angiogenic agents [85-92]. These findings have to be considered with the caveat that MSCs are also capable of exerting pro-tumorigenic effects and that MSCs should be reliably tracked once administered [38]. "
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    • "NSCs can be harvested from fetal, neonatal, or postnatal issues [12]. Since it is not feasible to obtain and isolate NSCs in sufficient numbers, immortalized neural progenitor cell lines instead of NSCs were prepared and used in several preclinical studies of prodrug cancer gene therapy [11, 13–15]. The well-characterized NSC line is HB1.F3, which was derived from fetal brain at 15 weeks of gestation and is known to be multipotent, migratory, and nontumorigenic. "
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