In vitro evaluation of targeted antisense 177Lu radiotherapy.

BACKGROUND

The BCL2 proto-oncogene in non-Hodgkin's lymphoma is a dominant inhibitor of apoptosis. The goal of this work was to develop a (177)Lu-labeled anti-BCL2-peptide nucleic acid (PNA) conjugate designed for dual modality NHL therapy, i.e., simultaneous down-regulation of BCL2-mediated resistance to apoptosis and delivery of cytotoxic internally emitted radiation.

MATERIALS AND METHODS

The effect of 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetra-acetic acid (DOTA)-anti-BCL2-Tyr(3)-octreotate was evaluated by uptake, efflux, proliferation, and viability assays, using Mec-1 lymphoma cells. In vitro dosimetry was modeled with a Monte Carlo projection.

RESULTS

Cellular efflux indicated moderate retention of radioactivity in the Mec-1 cells. Viability studies using the (177)Lu-labeled PNA conjugate indicated a mass-dose dependence and strongly additive statistical effect in reducing cellular viability.

CONCLUSION

These studies demonstrate the ability of a BCL2 antisense PNA conjugate to specifically target, be retained in, and reduce cellular viability in Mec-1 NHL cells. The results also hold promise for the development of a therapeutic radiopharmaceutical with potential dual modality function.