Cancer suicide gene therapy with TK.007: superior killing efficiency and bystander effect.
Standard
Cancer suicide gene therapy with TK.007: superior killing efficiency and bystander effect. / Preuß, Ellen; Muik, Alexander; Riecken, Kristoffer; Otte, Jürgen; von Laer, Dorothee; Fehse, Boris.
In: J MOL MED, Vol. 89, No. 11, 11, 2011, p. 1113-1124.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Cancer suicide gene therapy with TK.007: superior killing efficiency and bystander effect.
AU - Preuß, Ellen
AU - Muik, Alexander
AU - Riecken, Kristoffer
AU - Otte, Jürgen
AU - von Laer, Dorothee
AU - Fehse, Boris
PY - 2011
Y1 - 2011
N2 - Suicide gene therapy is a promising concept in oncology. We have recently introduced a novel suicide gene, TK.007, which was shown to excel established herpes simplex virus thymidine kinase (HSVtk) variants when used for donor-lymphocyte modification in adoptive immunotherapy models. Here, the potential of TK.007 in killing cancer cells was studied. Initially, we transduced tumour cell lines derived from different neoplasias (glioblastoma, melanoma, lung cancer, colon cancer) with lentiviral LeGO vectors encoding TK.007 or the splice-corrected (sc)HSVtk together with an eGFP/Neo-marker. Based on direct in vitro comparison, we found that TK.007 facilitates more efficient tumour cell killing at significantly lower ganciclovir doses in all tumour cell lines tested. Also, using different readout systems, we found a significantly stronger bystander effect of TK.007 as compared to scHSVtk. Importantly, in vitro data were confirmed in vivo using a subcutaneous G62 glioblastoma model in NOD/SCID mice. In mice transplanted with scHSVtk-positive tumours, treatment with low (10 mg/kg) or standard (50 mg/kg) ganciclovir doses resulted only in short-term growth inhibition or transient tumour remission, respectively. In striking contrast, in the TK.007 group, all animals achieved continuous complete remission after both standard and low-dose ganciclovir. Finally, a substantial bystander effect for TK.007 was also confirmed with the G62 model in vivo, where significantly prolonged survival for mice bearing tumours containing only 10% or 50% TK.007-expressing cells was observed. In summary, our data indicate strongly improved anti-tumour activity of TK.007 as compared to conventional HSVtk. We therefore suppose that TK.007 is an excellent candidate for cancer suicide gene therapy.
AB - Suicide gene therapy is a promising concept in oncology. We have recently introduced a novel suicide gene, TK.007, which was shown to excel established herpes simplex virus thymidine kinase (HSVtk) variants when used for donor-lymphocyte modification in adoptive immunotherapy models. Here, the potential of TK.007 in killing cancer cells was studied. Initially, we transduced tumour cell lines derived from different neoplasias (glioblastoma, melanoma, lung cancer, colon cancer) with lentiviral LeGO vectors encoding TK.007 or the splice-corrected (sc)HSVtk together with an eGFP/Neo-marker. Based on direct in vitro comparison, we found that TK.007 facilitates more efficient tumour cell killing at significantly lower ganciclovir doses in all tumour cell lines tested. Also, using different readout systems, we found a significantly stronger bystander effect of TK.007 as compared to scHSVtk. Importantly, in vitro data were confirmed in vivo using a subcutaneous G62 glioblastoma model in NOD/SCID mice. In mice transplanted with scHSVtk-positive tumours, treatment with low (10 mg/kg) or standard (50 mg/kg) ganciclovir doses resulted only in short-term growth inhibition or transient tumour remission, respectively. In striking contrast, in the TK.007 group, all animals achieved continuous complete remission after both standard and low-dose ganciclovir. Finally, a substantial bystander effect for TK.007 was also confirmed with the G62 model in vivo, where significantly prolonged survival for mice bearing tumours containing only 10% or 50% TK.007-expressing cells was observed. In summary, our data indicate strongly improved anti-tumour activity of TK.007 as compared to conventional HSVtk. We therefore suppose that TK.007 is an excellent candidate for cancer suicide gene therapy.
KW - Animals
KW - Humans
KW - Mice
KW - Cell Line, Tumor
KW - Dose-Response Relationship, Drug
KW - Neoplasm Transplantation
KW - Transplantation, Heterologous
KW - Mice, SCID
KW - Xenograft Model Antitumor Assays
KW - Mice, Inbred NOD
KW - Antiviral Agents/pharmacology
KW - Bystander Effect
KW - Ganciclovir/pharmacology
KW - Gene Therapy/methods
KW - Genes, Transgenic, Suicide
KW - Neoplasms/ethnology/genetics/pathology/therapy
KW - Simplexvirus/enzymology/genetics
KW - Thymidine Kinase/genetics/metabolism
KW - Viral Proteins/genetics/metabolism
KW - Animals
KW - Humans
KW - Mice
KW - Cell Line, Tumor
KW - Dose-Response Relationship, Drug
KW - Neoplasm Transplantation
KW - Transplantation, Heterologous
KW - Mice, SCID
KW - Xenograft Model Antitumor Assays
KW - Mice, Inbred NOD
KW - Antiviral Agents/pharmacology
KW - Bystander Effect
KW - Ganciclovir/pharmacology
KW - Gene Therapy/methods
KW - Genes, Transgenic, Suicide
KW - Neoplasms/ethnology/genetics/pathology/therapy
KW - Simplexvirus/enzymology/genetics
KW - Thymidine Kinase/genetics/metabolism
KW - Viral Proteins/genetics/metabolism
M3 - SCORING: Journal article
VL - 89
SP - 1113
EP - 1124
JO - J MOL MED
JF - J MOL MED
SN - 0946-2716
IS - 11
M1 - 11
ER -
