Early assessment of tumor response to JAC106, an anti-tubulin agent, by 3’-deoxy-3’-[18F]fluorothymidine using preclinical tumor models

Objectives We determined whether [18F]fluorothymidine ([18F]FLT)-positron emission tomography (PET) can detect early effects on tumor proliferation of JAC106, a new anti-tubulin agent.

Methods The effects on tubulin, viability, cell cycle, [18F]FLT uptake, and TK1 activity by JAC106 were measured in SW620 and KB-V1 cells. Dose-dependent anti-tumor effects of JAC106 were monitored by measuring tumor growth and by dynamic [18F]FLT-PET imaging in mice.Proliferation status of tumor was examined.

Results JAC106 potently inhibited tubulin polymerization, [3H]colchicine binding, and survival of SW620 (P<0.001, half maximal inhibitory concentration, IC50=3.15±1.4) and KB-V1 (P<0.01, IC50=21.84±24.59) cells. Exposure to JAC106 induced mitotic arrest starting at 18 hr and dose-dependently increased [18F]FLT uptake/1×105 cells (P<0.05) and TK1 activity and expression in vitro. Administration of 30 mg/kg JAC106 to mice inhibited the growth of SW620 and KB-VI tumors (%T/C, 3.34% and 20.6%, respectively), and changed the standardized uptake value of [18F]FLT by 77.9±22.4% (P=0.059) and 43.2±14.0% (P<0.01), respectively, on day 3 relative to day 0. JAC106 significantly decreased the number of Ki67-positive cells, TK1 activity, the cell fraction in G0G1 phase, and tumor expression of cyclins E, A, and B1 on day 3.

Conclusions [18F]FLT-PET can be used to monitor JAC106 inhibition of tumor growth, beginning 3 days after treatment in [18F]FLT uptake-favorable tumors. Incorporation of [18F]FLT-PET may be useful in the early clinical development of JAC106.

Research Support This study was supported by Korea Healthcare Technology R&D Project (No. A062254) and by the Real Time Molecular Imaging Research Program, Republic of Korea