title: Gene-directed enzyme prodrug therapy for osteosarcoma: sensitization to CPT-11 in vitro and in vivo by adenoviral delivery of a gene encoding secreted carboxylesterase-2.
abstract: Despite improvement in the treatment of osteosarcoma (OS), there are still many patients who cannot benefit from current treatment modalities. This warrants exploration of new treatment options. To that end, we investigated gene-directed enzyme prodrug therapy (GDEPT) with the use of human liver carboxylesterase-2 (CE2) and the anticancer agent CPT-11. CPT-11 is a clinically approved prodrug that needs to be metabolized into the active drug SN-38 by CEs, which occurs rather inefficiently in humans. GDEPT aims at high production of CE2 at the tumor site, resulting in efficient local conversion of CPT-11 into SN-38. Here, we show that OS cells transduced with an adenoviral vector containing the cDNA encoding a secreted form of CE2 (Ad-sCE2) expressed and efficiently secreted CE2. In vitro, transduction of a panel of OS cell lines with Ad-sCE2 resulted in sensitization up to 2800-fold to CPT-11 treatment. Primary OS short-term cultures, derived from patients suffering from a classic high-grade OS, demonstrated increased CPT-11 sensitivity up to 70-fold after transduction with Ad-sCE2 in vitro. When mice bearing s.c. MG-63 OS xenografts were intratumorally injected with Ad-sCE2 and CPT-11, this resulted in a significant difference in time to reach 2000 mm(3) in tumor volume as compared with animals receiving Ad-sCE2 or CPT-11 treatment (P < 0.05). Taken together, these data suggest that OS cells are sensitive for the combination of Ad-sCE2 and CPT-11.
authors.affiliation: Division of Gene Therapy, Department of Medical Oncology, VU University Medical Center, 1007 MB, Amsterdam, The Netherlands.
authors.forename: Dinja
authors.initials: D
authors.lastname: Oosterhoff
authors.forename: M Adhiambo
authors.initials: MA
authors.lastname: Witlox
authors.forename: Victor W
authors.initials: VW
authors.lastname: van Beusechem
authors.forename: Hidde J
authors.initials: HJ
authors.lastname: Haisma
authors.forename: Gerard R
authors.initials: GR
authors.lastname: Schaap
authors.forename: Johannes
authors.initials: J
authors.lastname: Bras
authors.forename: Frank A
authors.initials: FA
authors.lastname: Kruyt
authors.forename: Bonnie
authors.initials: B
authors.lastname: Molenaar
authors.forename: Epie
authors.initials: E
authors.lastname: Boven
authors.forename: Paul I J M
authors.initials: PI
authors.lastname: Wuisman
authors.forename: Herbert M
authors.initials: HM
authors.lastname: Pinedo
authors.forename: Winald R
authors.initials: WR
authors.lastname: Gerritsen
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000627:therapeutic use; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D043182:Carboxylesterase / Q000235:genetics* / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D012516:Osteosarcoma / Q000628:therapy*; D011355:Prodrugs / Q000627:therapeutic use*; D014161:Transduction, Genetic; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D011355:Prodrugs; D000077146:Irinotecan; D043182:Carboxylesterase; D002166:Camptothecin