In vitro assessment of novel transcription inhibitors and topoisomerase poisons in rhabdomyosarcoma cell lines.

PURPOSE: 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.

[Synthesis and antibacterial activity of the new 9-aminoacridine, 10,11-dihydro-5H-dibenzo[b,f]azepine, polyfluoro 5,6-dihydro-1,3,5-oxadiazine derivatives]. / Sintez i issledovanie antibacterial'noi aktivnosti novykh proizvodnykh 9-aminoakridina, 10,11-digidro-5H-dibenzo[b,f]azepina, poliftorirovannykh 5,6-digidro-1,3,5-oksadiazinov.

Screening among 9-aminoacridine, 10,11-dihydro-5H-dibenz[b, f]azepine and polyfluoro 5,6-dihydro-1,3,5-oxadiazine derivatives allowed to isolate compounds with potential antibacterial activity. Schemes of the active compounds synthesis are given. The most important is the estimation of the oxydiazines activity against gram-positive microorganisms including methicillin-resistant staphylococci. Special attention is paid to the activity of iminodibenzyl derivatives against multiresistant gram-negative microorganisms.

Inhibition of DNA repair synthesis in the rat by in vivo exposure to psychotropic drugs and reversal of the effect by co-administration with alpha-tocopherol.

Changes in unscheduled DNA synthesis (UDS) in lymphocytes and lipid peroxidation (LPO) in the rat brain regions cortex, hippocampus and hypothalamus were studied after 12 months of treatment with the neuroleptic fluphenazine (5 mg/kg b.w.), lithium (0.05% in drinking water), alpha-tocopherol (alpha-TP, 0.01% in drinking water) and the anticholinergic drug 7-methoxytacrine (0.1 and 1.0 g/kg in the diet). Fluphenazine and lithium suppressed UDS and increased LPO in cortex and hypothalamus. 7-Methoxy-tacrine at the lower dose stimulated UDS, at the higher dose it suppressed UDS after 6 months of exposure. Simultaneous administration of alpha-TP with fluphenazine suppressed the increase in LPO and the decrease in UDS produced by the neuroleptic alone. alpha-TP plasma levels were increased in groups administered alpha-TP as well as the levels in the hippocampus. Results indicate that the damage of biomembranes and the DNA repair enzymatic system as a consequence of fluphenazine action may be eliminated by the simultaneous administration of alpha-TP.

Mutagenic activity of some 9-aminoalkyl acridine derivatives on S. typhimurium.

The mutagenic potential of 9-(3'-dimethylaminopropylamino)-acridine and of its 1-nitro and 2-nitro derivatives was investigated by using histidine-requiring mutants of Salmonella typhimurium. The 9-(3'-dimethylaminopropylamino)-acridine exhibited a weak mutagenic activity only on one of the S. typhimurium tester strains, TA1537. The 1-nitro derivative induced mutations with high frequency in strains TA1537, TA1538 and TA98, whereas the 2-nitro derivative was substantially more mutagenic than the parent compound but it was much less mutagenic than the 1-nitro derivative. Pre-mutational damages made by the 1-nitro derivative were repaired by the uvrB gene-repair system, whereas those caused by the 2-nitro derivative could not be repaired by this system. Both the 1-nitro and 2-nitro derivatives induced some mutations in the base-pair substitution strain TA100 carrying a plasmid. The frequency of the his+ mutation induced both by 1-nitro and by the 2-nitro derivatives in strain TA101 lacking a nitro reductase was lower. These results emphasize the involvement of the nitro group in the interaction of acridine derivatives with the bacterial genome.