In vivo and in vitro assessment of the action of SN 28049, a benzonaphthyridine derivative targeting topoisomerase II, on the murine Colon 38 carcinoma.
OBJECTIVE
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.


CONCLUSIONS
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.
Chen
Ying Yi
YY
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
Finlay
Graeme J
GJ
Kirker
James A
JA
Marshall
Elaine S
ES
Richardson
Emma
E
Baguley
Bruce C
BC
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D004249:DNA Damage / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D009287:Naphthyridines / Q000008:administration & dosage / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects
D000970:Antineoplastic Agents; C533598:N-(2-(dimethylamino)ethyl)-2,6-dimethyl-1-oxo-1,2-dihydroxybenzo(b)-1,6-naphthyridine-4-carboxamide; D009287:Naphthyridines; D005047:Etoposide; D004250:DNA Topoisomerases, Type II