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

Abstract

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. [Cancer Res 2007;67(1):22-5]

Therapeutic targeting of subdural medulloblastomas using human neural stem cells expressing carboxylesterase

“…8,11,12 We have previously demonstrated that F3 human NSCs expressing the cytosine deaminase prodrug gene are endowed with selective migratory capacity and therapeutic effects against brain metastases from breast cancer. 11 Similarly, we reported that F3 NSCs transduced with the cytosine deaminase gene exhibit tropism and bystander killing effects for leptomeningeal medulloblastomas.…”

“…[20][21][22] HB1.F3.rCE (F3.rCE) cells were prepared by transduction with replication-deficient retrovirus that harbor the pLPCX vector, which contains the rCE gene. 12 Vectors were packaged by co-transduction of the rCE puromycin plasmid with the MV12 envelope-coding plasmid cDNA into pA317 cells. The retroviral supernatant was used for multiple infections of F3 cells.…”

“…[7][8][9] In addition, NSCs can target brain metastasis in leptomeningeal medulloblastoma, breast cancer, melanoma and disseminated neuroblastoma. 8,[10][11][12] Therefore, we adopted NSCs as a targeting delivery system for subdural medulloblastomas, which serves as a disseminated tumor model. Gene-directed enzyme prodrug therapy has been one of the therapeutic strategies in stem cell-based gene therapy.…”

“…15 The activation level of CPT-11 in human plasma is very low because of the lack of CE activity in human blood. 16 As a result, a rabbit liver CE (rCE) that is 100-fold more efficient than human CE 10,12,[17][18][19] can be used for enzyme and prodrug therapy in combination with CPT-11 to improve therapeutic efficacy. 17,19 In the present study, we administered rCE expressing NSCs intravenously (i.v.)…”

Glioma cancer stem cells and their role in therapy

“…Thanks to their non imunogenic character, allogeneic MSCs can substitute for autologous stem cells. We and others (Danks et al, 2007;Nakamura et al, 2004;Nakamizo et al, 2005) are encouraged by the results of stem cell driven enzyme prodrug therapy experiments to treat glioblastoma multiforme, a tumor with fatal prognosis. Our experiments took the advantage of the fact that human AT-MSCs are not immunogenic in treatment of rat glioblastoma C6 growing intracebroventriculary.…”