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

We determined whether [F-18]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 [H-3]colchicine binding were assessed in vitro. The effects of JAC106 on cytotoxicity, mitotic arrest, [F-18]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 [F-18]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 [F-18]FLT uptake/1 x 10(5) 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 [F-18]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 G(0)G(1) phase, and tumor expression of cyclins E, A, and B1 on day 3. [F-18]FLT PET can be used to monitor JAC106 inhibition of tumor growth, beginning 3 days after treatment. Incorporation of [F-18]FLT PET may be useful in the early clinical development of JAC106.