Search

Conditionally replicating adenoviruses (CRAds) were developed as new tools for cancer therapy. CRAds specifically replicate in and kill cancer cells. Within a solid tumor mass, release of newly formed infectious particles from infected cancer cells allows additional cell layers to be infected and destroyed. When used as monotherapeutic agents, CRAds showed only limited effects in clinical trials. Combination studies consisting of CRAd virotherapy with chemo-, radio-or enzyme prodrug therapy, however, showed additive or even synergistic effects and encouraging results in clinical studies. Furthermore, increased CRAd efficacy could be achieved in preclinical models by targeting CRAd infection specifically to tumor cells or via insertion of therapeutic genes in the CRAd genome. In this review, different mechanisms to achieve CRAd specificity, the efficacy of CRAds in clinical trials and ways to enhance their oncolytic potency are discussed.

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.

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.

promotiedatum: 24-11-2014 � prom-id: 11830