Antitumor activity of TZT-1027 (Soblidotin).
BACKGROUND
TZT-1027 (Soblidotin), a newly synthesized dolastatin 10 derivative that depolymerizes microtubules, has potent antitumor activity.


METHODS
Cell-killing kinetic analysis was performed by the colony-forming assay and the kinetics of TZT-1027 were compared with those of neocarzinostatin, adriamycin and vincristine, known to be typical concentration-, AUC- and time-dependent agents, respectively. DNA fragmentation was detectable by electrophoresis, cytotoxicity was evaluated by MTT assay and antitumor activity was examined by measuring the tumor weight after treatment.


RESULTS
TZT-1027 exhibited its cytocidal and apoptosis-inducing activity in a time-dependent manner. Its growth-inhibitory effect was less affected by overexpression of P-glycoprotein than that of other tubulin inhibitors and was not affected by the overexpression of breast cancer resistance protein or multidrug resistance-associated protein. TZT-1027 exhibited potent antitumor activities in an in vivo tumor model in which vincristine and docetaxel failed to show effectiveness.


CONCLUSIONS
Because its growth-inhibitory and antitumor activities were superior to those of the other drugs tested, including the tubulin inhibitors paclitaxel, docetaxel and vincristine, TZT-1027 should be useful in the chemotherapy of tumors that are not responsive to other tubulin inhibitors.
Watanabe
Junichi
J
ASKA Pharmaceutical Co., Ltd., R&D Administration, 1604 Shimosakunobe, Kawasaki-shi, Kanagawa 213-8522 Takatsu-ku, Japan. watanabe-j@aska-pharma.co.jp
Minami
Megumi
M
Kobayashi
Motohiro
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D053938:DNA Fragmentation / Q000187:drug effects; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005354:Fibrosarcoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000378:metabolism; D009842:Oligopeptides / Q000493:pharmacokinetics / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D009842:Oligopeptides; C116614:ABCG2 protein, human; C105791:soblidotin