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Division of Gene Therapy, Department of Medical Oncology, VU University Medical Center, 1007 MB, Amsterdam [D. O., V. W. v. B., F. A. K., B. M., E. B., H. M. P., W. R. G.]; Department of Orthopaedics, VU University Medical Center, 1007 MB, Amsterdam [M. A. W., P. I. J. M. W.]; Department of Therapeutic Gene Modulation, University Center for Pharmacy, 9713 AV, Groningen, [H. J. H.]; Department of Orthopedic Surgery, Academical Medical Center, 1100 AV, Amsterdam [G. R. S.]; and Department of Pathology, Academical Medical Center, 1100 AV, Amsterdam [J. B.], the Netherlands

³ To whom requests for reprints should be addressed, at Division of Gene Therapy, Department of Medical Oncology, VU University Medical Center, P. O. Box 7057, 1007 MB Amsterdam, the Netherlands. Phone: 31-20-4444319; Fax: 31-20-4448168; E-mail: winald.gerritsen{at}vumc.nl

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 mm³ 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.

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