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.

• Authors: Mary K Danks, K Jin Yoon, Rebecca A Bush, Joanna S Remack, Monika Wierdl, Lyudmila Tsurkan, Seung U Kim, Elizabeth Garcia, Marianne Z Metz, Joseph Najbauer, Philip M Potter, Karen S Aboody
• Journal: Cancer research (Cancer Res) Vol. 67 Issue 1 Pg. 22-5 (Jan 01 2007) ISSN: 0008-5472 [Print] United States
• PMID: 17210679 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• DNA, Complementary
• Prodrugs
• Irinotecan
• Carboxylesterase
• Camptothecin

Topics

• Adenoviridae (genetics)
• Animals
• Antineoplastic Agents, Phytogenic (pharmacokinetics, pharmacology)
• Camptothecin (analogs & derivatives, pharmacokinetics, pharmacology)
• Carboxylesterase (biosynthesis, genetics, metabolism)
• Cell Line, Tumor
• Combined Modality Therapy
• DNA, Complementary (administration & dosage, genetics)
• Disease-Free Survival
• Genetic Therapy (methods)
• Humans
• Irinotecan
• Mice
• Neuroblastoma (drug therapy, enzymology, genetics, therapy)
• Prodrugs (pharmacokinetics, pharmacology)
• Telencephalon (cytology, enzymology, physiology)
• Transduction, Genetic
• Xenograft Model Antitumor Assays