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

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

Inhibition of tubulin polymerization and [³H]colchicine binding were assessed in vitro. The effects of JAC106 on cytotoxicity, mitotic arrest, [¹⁸F]FLT uptake, and thymidine kinase 1 (TK1) activity were examined in SW620 and KB-V1 cells. Dose-dependent antitumor effects of JAC106 were monitored by measuring tumor growth and by dynamic [¹⁸F]FLT PET imaging in mice bearing SW620 and KB-V1 tumors. The proliferation status of tumors was examined.

JAC106 potently inhibited tubulin polymerization and decreased the viability 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 h 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). The baseline standardized uptake values (SUV) of SW620 and KB-V1 tumors were 0.96 ± 0.31 and 2.29 ± 0.70, respectively, with a significant difference (p < 0.01). After 3 days of treatment with 30 mg/kg JAC106, the [¹⁸F]FLT SUVs of SW620 and KB-V1 tumors, normalized to those before treatment, were 77.9 ± 22.4% (p = 0.059) and 43.2 ± 14.0% (p < 0.01), respectively. JAC106 significantly decreased the number of Ki-67-positive cells, TK1 activity, cell fraction in G₀G₁ phase, and tumor expression of cyclins E, A, and B1 on day 3.

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