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Antitumor Activity of TZT‐1027, a Novel Doiastatin 10 Derivative

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 injectio...

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Autores principales: Kobayashi, Motohiro, Natsume, Tsugitaka, Tamaoki, Satoru, Watanabe, Jun‐ichi, Asano, Hajime, Mikami, Takashi, Miyasaka, Katsuhiko, Miyazaki, Koichi, Gondo, Masaaki, Sakakibara, Kyoichi, Tsukagoshi, Shigeru
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Blackwell Publishing Ltd 1997
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5921373/
https://www.ncbi.nlm.nih.gov/pubmed/9140117
http://dx.doi.org/10.1111/j.1349-7006.1997.tb00383.x
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author Kobayashi, Motohiro
Natsume, Tsugitaka
Tamaoki, Satoru
Watanabe, Jun‐ichi
Asano, Hajime
Mikami, Takashi
Miyasaka, Katsuhiko
Miyazaki, Koichi
Gondo, Masaaki
Sakakibara, Kyoichi
Tsukagoshi, Shigeru
author_facet Kobayashi, Motohiro
Natsume, Tsugitaka
Tamaoki, Satoru
Watanabe, Jun‐ichi
Asano, Hajime
Mikami, Takashi
Miyasaka, Katsuhiko
Miyazaki, Koichi
Gondo, Masaaki
Sakakibara, Kyoichi
Tsukagoshi, Shigeru
author_sort Kobayashi, Motohiro
collection PubMed
description 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 rake 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/Ag 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 lμng carcinomas. TZT‐1027 at 10 μM almost completely inhibited the assembly of porcine brain microtubules. Therefore, its mechanism of antitumor action seems to he, at least in part, ascrihable to the inhibition of microtubule assembly. Because of its good preclinical activity, TZT‐1027 has been entered into phase I clinical trials.
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spelling pubmed-59213732018-05-11 Antitumor Activity of TZT‐1027, a Novel Doiastatin 10 Derivative Kobayashi, Motohiro Natsume, Tsugitaka Tamaoki, Satoru Watanabe, Jun‐ichi Asano, Hajime Mikami, Takashi Miyasaka, Katsuhiko Miyazaki, Koichi Gondo, Masaaki Sakakibara, Kyoichi Tsukagoshi, Shigeru Jpn J Cancer Res Article 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 rake 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/Ag 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 lμng carcinomas. TZT‐1027 at 10 μM almost completely inhibited the assembly of porcine brain microtubules. Therefore, its mechanism of antitumor action seems to he, at least in part, ascrihable to the inhibition of microtubule assembly. Because of its good preclinical activity, TZT‐1027 has been entered into phase I clinical trials. Blackwell Publishing Ltd 1997-03 /pmc/articles/PMC5921373/ /pubmed/9140117 http://dx.doi.org/10.1111/j.1349-7006.1997.tb00383.x Text en
spellingShingle Article
Kobayashi, Motohiro
Natsume, Tsugitaka
Tamaoki, Satoru
Watanabe, Jun‐ichi
Asano, Hajime
Mikami, Takashi
Miyasaka, Katsuhiko
Miyazaki, Koichi
Gondo, Masaaki
Sakakibara, Kyoichi
Tsukagoshi, Shigeru
Antitumor Activity of TZT‐1027, a Novel Doiastatin 10 Derivative
title Antitumor Activity of TZT‐1027, a Novel Doiastatin 10 Derivative
title_full Antitumor Activity of TZT‐1027, a Novel Doiastatin 10 Derivative
title_fullStr Antitumor Activity of TZT‐1027, a Novel Doiastatin 10 Derivative
title_full_unstemmed Antitumor Activity of TZT‐1027, a Novel Doiastatin 10 Derivative
title_short Antitumor Activity of TZT‐1027, a Novel Doiastatin 10 Derivative
title_sort antitumor activity of tzt‐1027, a novel doiastatin 10 derivative
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5921373/
https://www.ncbi.nlm.nih.gov/pubmed/9140117
http://dx.doi.org/10.1111/j.1349-7006.1997.tb00383.x
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