Evaluation of targeted antisense radiotherapy of non-Hodgkin’s lymphoma following a fractionated dose regimen

Objectives Our previous studies have successfully applied the radiometal-labeled DOTA-anti-bcl-2-PNA (peptide nucleic acid)-Tyr3-octreotate antisense conjugate for specific targeting of Mec-1 human non-Hodgkin’s lymphoma tumor xenografts through mRNA binding for molecular imaging in a mouse model. The two-fold goal of this project is to determine the maximum tolerated dose (MTD) of a 177Lu-anti-bcl-2-PNA-Tyr3-octreotate conjugate in mice, and second, to compare the treatment efficacy of mice bearing human Mec-1 tumor xenografts following a single or fractionated dose regimen.

Methods DOTA-anti-bcl-2-PNA-Tyr3-octreotate was labeled with 177Lu as the radiotherapy agent. 0-1000 µCi of the radiopharmaceutical was administered via tail vein in five groups of mice (n=5). Mice were observed daily for toxic symptoms according to weight, body condition score, and other signs over a duration of 84 days. MTD was determined as the dose with no toxicity shown in any mouse of the treated group. For the therapy study, mice bearing human Mec-1 tumor xenografts (n≥12/ group) were either administered a single MTD or 4 weekly fractionated doses of ¼ MTD. Normal saline was administered as a control. Mice were monitored and tumor volumes were determined by caliper measurements and calculated daily.

Results 500 µCi of the radiopharmaceutical was determined as the MTD with no mouse of that group showing any weight loss or physical signs of toxicity. For the therapy study, no mice in any cohort of the group showed any radiotherapy-related systemic toxicity. The average tumor doubling time was 6.20, 10.66 and 13.8 days for saline, single MTD and fractionated dose group, respectively. The median time to progression of 1 cm3 tumor volumes was 11.5, 32 and 49 days for saline, single and fractionated dose group, respectively.

Conclusions The tumor growth curves for the therapy groups showed significance with P < 0.05, suggesting the advantage of fractionated doses over regular single dose regimen.