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Cancer Chemotherapy and Pharmacology

, Volume 49, Issue 1, pp 35–47 | Cite as

Enhanced antitumor activities of TZT-1027 against TNF-α or IL-6 secreting Lewis lung carcinoma in vivo

  • Tsugitaka Natsume
  • Yasuhiro Koh
  • Motohiro Kobayashi
  • Hisao Fukumoto
  • Fumiyuki Takahashi
  • Takashi Nakamura
  • Yuichiro Ohe
  • Nagahiro Saijo
  • Kazuto Nishio
Original Article

Abstract.

Purpose: TZT-1027, an antimicrotubule agent that inhibits the polymerization of tubulin, shows potent antitumor activity in various transplantable tumor models in vivo. The high antitumor activity of TZT-1027 prompted us to speculate that this compound may have a mode of action other than its antimicrotubule and antimitotic activities. To elucidate the interaction of antitumor cytokines with TZT-1027 in tumors in vivo, we examined the antitumor activity of this agent against various cytokine gene-transfected Lewis lung carcinoma (LLC) cells inoculated into C57BL/6 mice. Methods: In vitro growth inhibition was evaluated using the MTT assay, and in vivo activity was evaluated in subcutaneous models in C57BL/6 mice. The status of the vasculature in tumor tissues was evaluated immunohistochemically using anti-CD31 antibody. We used a cDNA macroarray to examine the gene expression profiles in tumor tissues removed from mice. Results: TZT-1027 at 3 mg/kg showed potent antitumor activity in Mock (LLC-Neo cells) inoculated mice with a T/C% value of 16%. TZT-1027 at 3 mg/kg showed more potent antitumor activity in LLC-TNF cells and LLC-IL6 cells with T/C% values of 4% and 3%, respectively. TZT-1027 treatment destroyed the tumor vasculature as well as tumor cells in LLC-TNF and LLC-IL6 tissues of mice treated with TZT-1027. The LLC-TNF and LLC-IL6 tissues of mice treated with TZT-1027 had in common the independent alteration of the non-histone chromosomal protein HMG-14 and transcription factor 1 for heat shock gene. Focusing on the gene regulation related to angiogenesis, the alteration in transcriptional factors such as ets family genes and homeobox family genes was remarkable. Conclusions: These factors are candidates as determinants of the enhanced TZT-1027 antitumor activity in relation to these cytokines.

TZT-1027 TNF-α IL-6 Angiogenesis Macroarray 

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Copyright information

© Springer-Verlag 2001

Authors and Affiliations

  • Tsugitaka Natsume
    • 1
  • Yasuhiro Koh
    • 2
  • Motohiro Kobayashi
    • 1
  • Hisao Fukumoto
    • 2
  • Fumiyuki Takahashi
    • 2
  • Takashi Nakamura
    • 2
  • Yuichiro Ohe
    • 3
  • Nagahiro Saijo
    • 3
  • Kazuto Nishio
    • 2
  1. 1.Pharmacological Research Department, Teikoku Hormone Mfg., Co. Ltd., 1604 Shimosakunobe, Takatsu-ku, Kawasaki-shi, Kanagawa 213-8522, Japan
  2. 2.Pharmacology Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
  3. 3.Medical Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan

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