soblidotin and Leukemia-P388

TZT-1027 (Soblidotin), an antimicrotubule agent, has been demonstrated to show potent antitumor effects, though the relationships among antitumor effect, cytotoxicity and anti-vascular effect of TZT-1027 have not been studied. We established in vivo human lung vascular-rich tumor models using a vascular endothelial growth factor-secreting tumor (SBC-3/VEGF). SBC-3/VEGF tumors exhibited a high degree of angiogenesis in comparison with the mock transfectant (SBC-3/Neo) tumors in a dorsal skinfold chamber model and grew much faster and larger than SBC-3/Neo tumors in the tumor growth study. The antitumor activity of antimicrotubule agents, including TZT-1027, was evaluated in both early- and advanced-stage SBC-3/Neo and SBC-3/VEGF tumor models to elucidate the relationship between the antitumor activity and anti-vascular effect of these agents. TZT-1027 exhibited potent antitumor activity against both early- and advanced-stage SBC-3/Neo and SBC-3/VEGF tumors, whereas combretastatin A4 phosphate did not. Vincristine and docetaxel exhibited potent antitumor activity against early-stage SBC-3/Neo and SBC-3/VEGF tumors, and advanced-stage SBC-3/Neo tumors, but did not exhibit activity against advanced-stage SBC-3/VEGF tumors. The difference in antitumor activity between these agents could be ascribed to differences in direct cytotoxicity and anti-vascular effect. Furthermore, a prominent accumulation of erythrocytes in the tumor vasculature, followed by leakage and scattering of these erythrocytes from the tumor vasculature, was observed after TZT-1027 administration to mice bearing advanced-stage SBC-3/VEGF tumors. These findings strongly suggest that TZT-1027 has a potent anti-vascular effect, in addition to direct cytotoxicity.

Topics: Animals; Antineoplastic Agents; Carcinoma, Small Cell; Cell Survival; Docetaxel; Erythrocytes; Female; Gene Expression Regulation, Neoplastic; Humans; Leukemia P388; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms, Experimental; Neovascularization, Pathologic; Oligopeptides; Skin; Stilbenes; Taxoids; Transfection; Vascular Endothelial Growth Factor A; Vincristine

Dolastatin 10, a pentapeptide isolated from the marine mollusk Dolabella auricularia, has antitumor activity. TZT-1027, a dolastatin 10 derivative, is a newly synthesized antitumor compound. We evaluated its antitumor activity against a variety of transplantable tumors in mice. Intermittent injections of TZT-1027 were more effective than single or repeated injections in mice with P388 leukemia and B16 melanoma. Consequently, TZT-1027 shows schedule dependency. TZT-1027 was effective against P388 leukemia not only when administered i.p., but also when given i.v. However, although TZT-1027 given i.v. was active against murine solid tumors, TZT-1027 administered i.p. was ineffective against all the tumors tested with the exception of colon 26 adenocarcinoma. The i.v. injection of TZT-1027 at a dose of 2.0 mg/kg remarkably inhibited the growth of three murine solid tumors; colon 26 adenocarcinoma, B16 melanoma and M5076 sarcoma, with T/C values of less than 6%. The antitumor activities of TZT-1027 against these tumors were superior or comparable to those of the reference agents; dolastatin 10, cisplatin, vincristine, 5-fluorouracil (5-FU) and E7010. In experiments with drug-resistant P388 leukemia, TZT-1027 showed good activity against cisplatin-resistant P388 and moderate activity against vincristine- and 5-fluorouracil-resistant P388, but no activity against adriamycin-resistant P388. TZT-1027 was also effective against human xenografts, that is, tumor regression was observed in mice bearing MX-1 breast and LX-1 lung carcinomas. TZT-1027 at 10 microM almost completely inhibited the assembly of porcine brain microtubules. Therefore, its mechanism of antitumor action seems to be, at least in part, ascribable to the inhibition of microtubule assembly. Because of its good preclinical activity, TZT-1027 has been entered into phase I clinical trials.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Division; Cisplatin; Crosses, Genetic; Depsipeptides; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Screening Assays, Antitumor; Female; Humans; Leukemia P388; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Nude; Mollusca; Neoplasms, Experimental; Oligopeptides; Transplantation, Heterologous