An efficient targeted radiotherapy/gene therapy strategy utilising human telomerase promoters and radioastatine and harnessing radiation-mediated bystander effects.
BACKGROUND
Targeted radiotherapy achieves malignant cell-specific concentration of radiation dosage by tumour-affinic molecules conjugated to radioactive atoms. Combining gene therapy with targeted radiotherapy is attractive because the associated cross-fire irradiation of the latter induces biological bystander effects upon neighbouring cells overcoming low gene transfer efficiency.


METHODS
We sought to maximise the tumour specificity and efficacy of noradrenaline transporter (NAT) gene transfer combined with treatment using the radiopharmaceutical meta-[(131)I]iodobenzylguanidine ([(131)I]MIBG). Cell-kill was achieved by treatment with the beta-decay particle emitter [(131)I]MIBG or the alpha-particle emitter [(211)At]MABG. We utilised our novel transfected mosaic spheroid model (TMS) to determine whether this treatment strategy could result in sterilisation of spheroids containing only a small proportion of NAT-expressing cells.


RESULTS
The concentrations of [(131)I]MIBG and [(211)At]MABG required to reduce to 0.1% the survival of clonogens derived from the TMS composed of 100% of NAT gene-transfected cells were 1.5 and 0.004 MBq/ml (RSV promoter), 8.5 and 0.0075 MBq/ml (hTR promoter), and 9.0 and 0.008 MBq/ml (hTERT promoter), respectively. The concentrations of radiopharmaceutical required to reduce to 0.1% the survival of clonogens derived from 5% RSV/NAT and 5% hTERT/NAT TMS were 14 and 23 MBq/ml, respectively, for treatment with [(131)I]MIBG and 0.018 and 0.028 MBq/ml, respectively, for treatment with [(211)At]MABG.


CONCLUSIONS
These results indicate that the telomerase promoters have the capacity to drive the expression of the NAT. The potency of [(211)At]MABG is approximately three orders of magnitude greater than that of [(131)I]MIBG. Spheroids composed of only 5% of cells expressing NAT under the control of the RSV or hTERT promoter were sterilised by radiopharmaceutical treatment. This observation is indicative of bystander cell-kill.
Department of Radiation Oncology and Targeted Therapy, Glasgow University, Cancer Research UK Beatson Laboratories, Glasgow G61 1BD, Scotland, UK.
Marie
M
Boyd
Robert J
RJ
Mairs
W Nicol
WN
Keith
Susan C
SC
Ross
Philip
P
Welsh
Gamal
G
Akabani
Jonathan
J
Owens
Ganesan
G
Vaidyanathan
Ross
R
Carruthers
Jennifer
J
Dorrens
Michael R
MR
Zalutsky
D001246:Astatine / Q000494:pharmacology*; D024201:Bystander Effect; D016923:Cell Death; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010957:Plasmids; D011401:Promoter Regions, Genetic; D019275:Radiopharmaceuticals / Q000494:pharmacology*; D011878:Radiotherapy / Q000379:methods*; D018874:Spheroids, Cellular; D027981:Symporters / Q000235:genetics; D019098:Telomerase / Q000235:genetics*; D014162:Transfection; D019076:Transgenes; D014407:Tumor Cells, Cultured
D050484:Norepinephrine Plasma Membrane Transport Proteins; D019275:Radiopharmaceuticals; C493227:SLC6A2 protein, human; D027981:Symporters; D019098:Telomerase; D001246:Astatine