title: Early assessment of tumor response to JAC106, an anti-tubulin agent, by 3'-deoxy-3'-[¹⁸F]fluorothymidine in preclinical tumor models.
abstract: OBJECTIVE
  We determined whether [(18)F]fluorothymidine (FLT) positron emission tomography (PET) can detect early effects on tumor proliferation of JAC106, a new anti-tubulin agent.
  
  
  METHODS
  Inhibition of tubulin polymerization and [(3)H]colchicine binding were assessed in vitro. The effects of JAC106 on cytotoxicity, mitotic arrest, [(18)F]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 [(18)F]FLT PET imaging in mice bearing SW620 and KB-V1 tumors. The proliferation status of tumors was examined.
  
  
  RESULTS
  JAC106 potently inhibited tubulin polymerization and decreased the viability of SW620 (p < 0.001, half maximal inhibitory concentration, IC(50) = 3.15 ± 1.4) and KB-V1 (p < 0.01, IC(50) = 21.84 ± 24.59) cells. Exposure to JAC106 induced mitotic arrest starting at 18 h and dose-dependently increased [(18)F]FLT uptake/1 × 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 [(18)F]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.
  
  
  CONCLUSIONS
  [(18)F]FLT PET can be used to monitor JAC106 inhibition of tumor growth, beginning 3 days after treatment. Incorporation of [(18)F]FLT PET may be useful in the early clinical development of JAC106.
authors.affiliation: Institute for Innovative Cancer Research, University of Ulsan College of Medicine, Asan Medical Center, Pungnap 2-dong, Songpa-gu, Seoul 138-736, Korea.
authors.forename: Seung Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Hye Young
authors.initials: HY
authors.lastname: Kang
authors.forename: Seog Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Jin Hwa
authors.initials: JH
authors.lastname: Chung
authors.forename: Seung Jun
authors.initials: SJ
authors.lastname: Oh
authors.forename: Jin-Sook
authors.initials: JS
authors.lastname: Ryu
authors.forename: Sung-Bae
authors.initials: SB
authors.lastname: Kim
authors.forename: Jong Soon
authors.initials: JS
authors.lastname: Kang
authors.forename: Song-Kyu
authors.initials: SK
authors.lastname: Park
authors.forename: Hwan Mook
authors.initials: HM
authors.lastname: Kim
authors.forename: Myung-Hwa
authors.initials: MH
authors.lastname: Kim
authors.forename: Dae Hyuk
authors.initials: DH
authors.lastname: Moon
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015224:Dideoxynucleosides; D006801:Humans; D008297:Male; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000201:enzymology / Q000473:pathology; D049268:Positron-Emission Tomography; D055503:Protein Multimerization / Q000187:drug effects*; D020836:Protein Structure, Quaternary; D013937:Thymidine Kinase / Q000378:metabolism; D013997:Time Factors; D014404:Tubulin / Q000737:chemistry*; D050257:Tubulin Modulators / Q000008:administration & dosage / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D015224:Dideoxynucleosides; D014404:Tubulin; D050257:Tubulin Modulators; D013937:Thymidine Kinase; C092717:thymidine kinase 1; C002854:alovudine