Open AccessTZT‐1027, an Antimicrotubule Agent, Attacks Tumor Vasculature and Induces Tumor Cell Death
Author(s) -
Otani Masashi,
Natsume Tsugitaka,
Watanabe Junichi,
Kobayashi Motohiro,
Murakoshi Masanori,
Mikami Takashi,
Nakayama Takaharu
Publication year - 2000
Publication title -
japanese journal of cancer research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 0910-5050
DOI - 10.1111/j.1349-7006.2000.tb01022.x
Subject(s) - medicine , apoptosis , in vivo , pathology , umbilical vein , tumor necrosis factor alpha , necrosis , cancer research , in vitro , biology , immunology , biochemistry , microbiology and biotechnology
TZT‐1027, a dolastatin 10 derivative, is an antimicrotubule agent with potent antitumor activity both in vitro and in vivo. In this study, we performed biochemical and histopathological examinations, and evaluated TZT‐1027‐induced tumoral vascular collapse and tumor cell death in an advanced tumor model, murine colon 26 adenocarcinoma. In addition, we studied the effects of TZT‐1027 on cultured human umbilical vein endothelial cells (HUVEC). Tolerable doses of TZT‐1027 induced tumor‐selective hemorrhage within 1 h. This hemorrhage occurred mainly in the peripheral area of the tumor mass. Measurements of tumoral hemoglobin content and dye permeation revealed that the hemorrhage occurred firstly and tumor blood flow stopped secondarily. The vascular damage was followed by continuous induction of apoptosis of the tumor cells, tumor tissue necrosis, and tumor regression. In cultured HUVEC, TZT‐1027 induced marked cell contraction with membrane blebbing in 30 min. These cell changes were completely inhibited by K252a, a broad‐spectrum inhibitor of protein kinases. These effects of TZT‐1027 on both tumor vasculature and HUVEC were greater than those of vincristine. In conclusion, TZT‐1027 quickly attacked the well‐developed vascular system of advanced tumors by a putative protein kinase‐dependent mechanism, and then blocked tumor blood flow. Therefore, TZT‐1027 has both a conventional antitumor activity and a unique anti‐tumoral vascular activity, making it a potentially powerful tool for clinical cancer therapy.