In vitro assessment of novel transcription inhibitors and topoisomerase poisons in rhabdomyosarcoma cell lines.
OBJECTIVE
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Current chemotherapy regimes include the topoisomerase II poison etoposide and the transcription inhibitor actinomycin D. Poor clinical response necessitate identification of new agents to improve patient outcomes.


METHODS
We assessed the in vitro cytotoxicity (MTT assay) of DNA intercalating agents in five established human RMS cell lines. These include novel classes of transcription inhibitors and topoisomerase poisons, previously shown to have potential as anti-cancer agents.


RESULTS
Amongst the former agents, bisintercalating bis(9-aminoacridine-4-carboxamides) linked through the 9-position, and bis(phenazine-1-carboxamides) linked via their side chains, are compared with established transcription inhibitors. Amongst the latter, monofunctional acridine-4-carboxamides related to N-[2-(dimethylamino)ethyl]acridine-4-carboxamide, DACA, are compared with established topoisomerase poisons.


CONCLUSIONS
Our findings specifically highlight the topoisomerase poison 9-amino-DACA, its 5-methylsulphone derivative, AS-DACA, and the bis(phenazine-1-carboxamide) transcription inhibitor MLN944/XR5944, currently in phase I trial, as candidates for further research into new agents for the treatment of RMS.
Wolf
Steven J
SJ
The Tumour Bank, Oncology Research Unit, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia.
Wakelin
Laurence P G
LP
He
Zhicong
Z
Stewart
Bernard W
BW
Catchpoole
Daniel R
DR
D000166:Acridines / Q000494:pharmacology; D000609:Aminoacridines / Q000494:pharmacology; D000951:Antigens, Neoplasm / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology*; D010619:Phenazines / Q000494:pharmacology; D012208:Rhabdomyosarcoma / Q000188:drug therapy* / Q000378:metabolism; D018232:Rhabdomyosarcoma, Alveolar / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D018233:Rhabdomyosarcoma, Embryonal / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D059003:Topoisomerase Inhibitors
D000166:Acridines; D000609:Aminoacridines; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D019384:Nucleic Acid Synthesis Inhibitors; D010619:Phenazines; D059003:Topoisomerase Inhibitors; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II