Antitumor activity of TZT-1027 (Soblidotin)

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

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.

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.

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.