Tumor-targeted enzyme/prodrug therapy mediates long-term disease-free survival of mice bearing disseminated neuroblastoma.
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.
Danks
Mary K
MK
Department of Molecular Pharmacology, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA. mary.danks@stjude.org
Yoon
K Jin
KJ
Bush
Rebecca A
RA
Remack
Joanna S
JS
Wierdl
Monika
M
Tsurkan
Lyudmila
L
Kim
Seung U
SU
Garcia
Elizabeth
E
Metz
Marianne Z
MZ
Najbauer
Joseph
J
Potter
Philip M
PM
Aboody
Karen S
KS
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D043182:Carboxylesterase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D018076:DNA, Complementary / Q000008:administration & dosage / Q000235:genetics; D018572:Disease-Free Survival; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D009447:Neuroblastoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000628:therapy*; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology*; D013687:Telencephalon / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D014161:Transduction, Genetic; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D018076:DNA, Complementary; D011355:Prodrugs; D000077146:Irinotecan; D043182:Carboxylesterase; D002166:Camptothecin