ANTITUMOR-ACTIVITY OF TZT-1027, A NOVEL DOLASTATIN 10 DERIVATIVE

Dolastatin 10, a pentapeptide isolated from the marine mollusk Dolabel la auricularia, has antitumor activity, TZT-1027, a dolastatin 10 deri vative, is a newly synthesized antitumor compound. We evaluated its an titumor activity against a variety of transplantable tumors in mice. I ntermittent injections of TZT-1027 were more effective than single or repeated injections in mice with P388 leukemia and B16 melanoma. Conse quently, TZT-1027 shows schedule dependency. TZT-1027 was effective ag ainst P388 leukemia not only when administered i.p., but also when giv en i,v. However, although TZT-1027 given i.v. was active against murin e 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 tile growth of three murine solid tumors; colon 26 adenocarcinoma, B1 6 melanoma and M5076 sarcoma, with T/C values of less than 6%. The ant itumor activities of TZT-1027 against these tumors were superior or co mparable to those of the reference agents; dolastatin 10, cisplatin, v incristine, 5-fluorouracil (5-FU) and E7010. In experiments with drag- resistant P388 leukemia, TZT-1027 showed good activity against cisplat in-resistant P388 and moderate activity against vincristine- and 5-flu orouracil-resisiant 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 lun g carcinomas. TZT-1027 at 10 mu M almost completely inhibited the asse mbly of porcine brain microtubules. Therefore, its mechanism of antitu mor action seems to be, at least in part, ascribable to the inhibition of microtubule assembly. Because of its good preclinical activity, TZ T-1027 has been entered into phase I clinical trials.