Internal radiotherapy of ¹⁸⁸Re-IDA-D-[c(RGDfK)]₂ in combination with bevacizumab or temozolomide in U87-MG tumor-bearing mice

Objectives The primary objective of this study were to investigate in vivo the antitumor effects of combination therapy of ¹⁸⁸Re-IDA-D-[c(RGDfK)]₂ ([¹⁸⁸Re]1) with low dose of temozolomide (TMZ) in the U87-MG tumor xenograft mouse model. A secondary objective was to demonstrate whether dual anti-angiogenic therapy with a low dose of [¹⁸⁸Re]1 plus bevacizumab (AVA) would be more effective than monotherapy with a high dose of [¹⁸⁸Re]1 in glioma.

Methods For an internal radio-therapeutic agent, [¹⁸⁸Re]1 was synthesized and prepared two different doses (3.7 and 11.1 MBq). The therapeutic effects of the drugs [combination therapy: [¹⁸⁸Re]1 (11.1 MBq) and TMZ (2 or 5 mg), dual anti-angiogenic therapy: [¹⁸⁸Re]1 (3.7 MBq) and AVA (2.5 mg)] in U87-MG tumor cells bearing Balb/C nude mice were assessed using tumor growth size measurement and histological examination. All mice were intravenously injected with [¹⁸⁸Re]1, TMZ, AVA or saline every 4th day over a period of 14 days, and monitored daily up to 2 weeks.

Results In combination therapy for 2 weeks, monotherapy with TMZ (2 and 5 mg) or [¹⁸⁸Re]1 (11.1 MBq) suppressed U87-MG tumor growth by as much as 63, 66, and 81%, respectively, compared to the saline treated group (p < 0.05). Remarkably, the combinatation treatment group with TMZ (2 mg) and [¹⁸⁸Re]1 (11.1 MBq) resulted in complete cessation of tumor growth (93% reduction in tumor size versus control). The dual anti-angiogenic treatment group with [¹⁸⁸Re]1 (3.7 MBq) and AVA (2.5 mg) showed marked anti-tumor growth effects with a reduction in tumor volume of 73% versus the monotherapy group with AVA or [¹⁸⁸Re]1 alone (33, 52%, respectively, p < 0.05). The anti-tumor effects were confirmed in an immunohistochemistry.

Conclusions The combination therapy of anticancer drugs with an internal radio-therapeutic agent presented more cytotoxic effects compared to the monotherapy of either drug. These results suggest that [¹⁸⁸Re]1 hold promise as a radio-therapeutic agent in the field of the combination protocol against glioblastoma.