Enhanced antitumor activities of TZT-1027 against TNF-alpha or IL-6 secreting Lewis lung carcinoma in vivo.
OBJECTIVE
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.
Natsume
Tsugitaka
T
Pharmacological Research Department, Teikoku Hormone Mfg., Co. Ltd., Kawasaki-shi, Kanagawa, Japan.
Koh
Yasuhiro
Y
Kobayashi
Motohiro
M
Fukumoto
Hisao
H
Takahashi
Fumiyuki
F
Nakamura
Takashi
T
Ohe
Yuichiro
Y
Saijo
Nagahiro
N
Nishio
Kazuto
K
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018827:Carcinoma, Lewis Lung / Q000235:genetics / Q000378:metabolism*; D018076:DNA, Complementary / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000378:metabolism*; D018374:LLC-PK1 Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D009842:Oligopeptides / Q000494:pharmacology*; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000302:isolation & purification; D013778:Tetrazolium Salts; D013844:Thiazoles; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D000970:Antineoplastic Agents; D018076:DNA, Complementary; D015850:Interleukin-6; D009842:Oligopeptides; D012334:RNA, Neoplasm; D013778:Tetrazolium Salts; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; C105791:soblidotin; C022616:thiazolyl blue