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

Abstract

We synthesized a potent new antitumor podophyllotoxin derivative (4beta-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 microg/ml and 0.26-8.9 microg/ml against marine 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.

• Authors: T Utsugi, J Shibata, Y Sugimoto, K Aoyagi, K Wierzba, T Kobunai, T Terada, T Oh-hara, T Tsuruo, Y Yamada
• Journal: Cancer research (Cancer Res) Vol. 56 Issue 12 Pg. 2809-14 (Jun 15 1996) ISSN: 0008-5472 [Print] United States
• PMID: 8665518 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents, Phytogenic
• DNA, Neoplasm
• TOP 53
• Topoisomerase II Inhibitors
• Etoposide

Topics

• Animals
• Antineoplastic Agents, Phytogenic (pharmacokinetics, therapeutic use)
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism, secondary)
• Colonic Neoplasms (pathology)
• DNA, Neoplasm (drug effects)
• Drug Screening Assays, Antitumor
• Etoposide (analogs & derivatives, pharmacokinetics, therapeutic use)
• Humans
• Lung Neoplasms (drug therapy, metabolism, secondary)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C3H
• Mice, Inbred C57BL
• Mice, Inbred DBA
• Mice, Nude
• Neoplasms, Experimental (drug therapy)
• Specific Pathogen-Free Organisms
• Topoisomerase II Inhibitors
• Tumor Cells, Cultured