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In vivo and in vitro assessment of the action of SN 28049, a benzonaphthyridine derivative targeting topoisomerase II, on the murine Colon 38 carcinoma.
MedLine Citation:
PMID:  20697772     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
Aim: SN 28049 (N-[2-(dimethylamino)ethyl]-2,6-dimethyl-1-oxo-1,2-dihydrobenzo[b]-1,6-naphthyridine-4-carboxamide) is a new DNA binding drug that targets topoisomerase II. SN 28049 is curative against the murine Colon 38 adenocarcinoma (CT38) while etoposide, another topoisomerase II-directed drug, shows minimal activity; we investigated the basis for this difference in vivo and in vitro. Methods: Colon 38 tumours were grown in C57Bl mice and in immunodeficient mice. Tumour sections were examined by staining and TUNEL assays. A new cell line (Co-38P) derived from the in vivo tumour was developed and responses were analysed using flow cytometry. Results: Both SN 28049 and etoposide induced similar tumour histological changes, reducing mitotic index and increasing apoptotic index 8 h after administration. At later times however, SN 28049-treated tumours showed further progressive morphological changes while etoposide-treated tumours reverted to their original growth characteristics. The effects of SN 28049 on tumour growth were delayed and attenuated when Colon 38 tumours were grown in immunodeficient mice. SN 28049 and etoposide both induced dose-dependent increases of γ-phosphorylation of histone H2AX and cell cycle perturbation of the Co-38P cell line, indicative of DNA damage, although SN 28049 had 30-fold higher activity. Following 1-hour drug exposure of Co-38P cells, SN 28049 was more effective that etoposide in inducing persistent cycle arrest for the same degree of DNA damage. Conclusion: The superior antitumour activity of SN 28049 may result from its ability to induce long term cycle arrest. Host immune responses contribute to the curative activity of SN 28049 and this could result from the induction of cycle arrest.
Authors:
Ying Yi Chen; Graeme J Finlay; James A Kirker; Elaine S Marshall; Emma Richardson; Bruce C Baguley
Publication Detail:
Type:  Journal Article     Date:  2010-08-10
Journal Detail:
Title:  Investigational new drugs     Volume:  29     ISSN:  1573-0646     ISO Abbreviation:  Invest New Drugs     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-09-13     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8309330     Medline TA:  Invest New Drugs     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1504-10     Citation Subset:  IM    
Affiliation:
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
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