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.