Antitumor activity of a novel podophyllotoxin derivative (TOP-53) against lung cancer and lung metastatic cancer

Teruhiro Utsugi, Jiro Shibata, Yoshikazu Sugimoto, Kumio Aoyagi, Konstanty Wierzba, Takashi Kobunai, Tadafumi Terada, Tomoko Oh-hara, Takashi Tsuruo, Yuji Yamada

Research output: Contribution to journalArticle

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Abstract

We synthesized a potent new antitumor podophyllotoxin derivative (4β- aminoalkyl-4'-O-demethyl-4-desoxypodophyllotoxin; TOP-53) in our search for a drug that has strong activity against lung cancer and lung metastatic cancer. TOP-53 exhibited twice the inhibitory activity of etoposide (VP-16) against topoisomerase II and induced DNA strand breaks but showed no inhibitory activity against tubulin polymerization. The in vitro cytotoxic activity of TOP-53 assessed as IC50 was 0.016-0.37 μg/ml and 0.26-8.9 μg/ml against murine tumor and human non-small cell lung cancer (NSCLC) cell lines, respectively. TOP-53 exerted significant efficacy equivalent to that of VP- 16 on s.c.-implanted murine solid tumors (Colon 26, B16-BL6, and Lewis lung carcinoma) at doses 3-5 times lower than that of VP-16. In human tumor xenografts using NSCLC, TOP-53 was active for four of five tumors, whereas VP-16 was active for two of five tumors. Potent inhibitory activity of TOP- 53 was also found against a lung tumor (Lewis lung carcinoma) and four lung metastatic tumors (NL-22 and NL-17 colon cancer, UV2237M fibrosarcoma, and K1735M2 melanoma). TOP-53 appeared to be more active against four of them than VP-16. Thus, TOP-53 is not only active against s.c.-implanted lung cancers but also strongly active against lung localized tumor and metastatic tumors in the lungs. The high selectivity of TOP-53 was attributed to its high distribution into the lung and its persistence. TOP-53 is expected to be highly effective against lung cancer including NSCLC and various lung metastatic tumors in the clinical field.

Original languageEnglish
Pages (from-to)2809-2814
Number of pages6
JournalCancer Research
Volume56
Issue number12
Publication statusPublished - 1996 Jun 15
Externally publishedYes

Fingerprint

Podophyllotoxin
Lung Neoplasms
Etoposide
Neoplasms
Lung
Non-Small Cell Lung Carcinoma
Lewis Lung Carcinoma
TOP 53
Type II DNA Topoisomerase
DNA Breaks
Fibrosarcoma
Tubulin
Heterografts
Polymerization
Colonic Neoplasms
Inhibitory Concentration 50
Melanoma
Colon

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Utsugi, T., Shibata, J., Sugimoto, Y., Aoyagi, K., Wierzba, K., Kobunai, T., ... Yamada, Y. (1996). Antitumor activity of a novel podophyllotoxin derivative (TOP-53) against lung cancer and lung metastatic cancer. Cancer Research, 56(12), 2809-2814.

Antitumor activity of a novel podophyllotoxin derivative (TOP-53) against lung cancer and lung metastatic cancer. / Utsugi, Teruhiro; Shibata, Jiro; Sugimoto, Yoshikazu; Aoyagi, Kumio; Wierzba, Konstanty; Kobunai, Takashi; Terada, Tadafumi; Oh-hara, Tomoko; Tsuruo, Takashi; Yamada, Yuji.

In: Cancer Research, Vol. 56, No. 12, 15.06.1996, p. 2809-2814.

Research output: Contribution to journalArticle

Utsugi, T, Shibata, J, Sugimoto, Y, Aoyagi, K, Wierzba, K, Kobunai, T, Terada, T, Oh-hara, T, Tsuruo, T & Yamada, Y 1996, 'Antitumor activity of a novel podophyllotoxin derivative (TOP-53) against lung cancer and lung metastatic cancer', Cancer Research, vol. 56, no. 12, pp. 2809-2814.
Utsugi, Teruhiro ; Shibata, Jiro ; Sugimoto, Yoshikazu ; Aoyagi, Kumio ; Wierzba, Konstanty ; Kobunai, Takashi ; Terada, Tadafumi ; Oh-hara, Tomoko ; Tsuruo, Takashi ; Yamada, Yuji. / Antitumor activity of a novel podophyllotoxin derivative (TOP-53) against lung cancer and lung metastatic cancer. In: Cancer Research. 1996 ; Vol. 56, No. 12. pp. 2809-2814.
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