Disease relevance of YTHDF1

• These data have implications for predicting activity and toxicity of DACA and support the use of PET early in drug development [1].
• Phase II study of XR5000 (DACA) administered as a 120-h infusion in patients with recurrent glioblastoma multiforme [2].
• Phase II study of XR5000 (DACA), an inhibitor of topoisomerase I and II, administered as a 120-h infusion in patients with advanced ovarian cancer [3].
• Phase II study of XR 5000 (DACA), an inhibitor of topoisomerase I and II, administered as a 120-h infusion in patients with non-small cell lung cancer [4].
• One patient given DACA through a central venous catheter experienced chest pain with transient electrocardiogram changes, but no evidence of myocardial infarction [5].

High impact information on YTHDF1

• PURPOSE: To evaluate tumor, normal tissue, and plasma pharmacokinetics of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) [1].
• The study aimed to determine the pharmacokinetics of carbon-11-labeled DACA ([11C]DACA) and evaluate the effect of pharmacologic doses of DACA on radiotracer kinetics [1].
• In the presence of unlabeled DACA, pharmacokinetics were altered in myocardium, spleen, and tumors [1].
• This study reports on the biodistribution and metabolism of the 11C-labeled novel antitumor agent N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) (also known as NSC 601316) in rats (plasma and tissues) and humans (plasma) [6].
• The overlap in selection with DACA and mAMSA or AMCA suggests that altered recognition of the acridine moiety may be involved in these mutations [7].

Chemical compound and disease context of YTHDF1

• The effect of DACA on the cytokinetics of cultured Lewis lung adenocarcinoma cells was compared with those of two clinical drugs of this class, doxorubicin and amsacrine [8].
• N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide dihydrochloride (DACA) is a topoisomerase II-targeted antitumour drug with curative activity against murine Lewis lung carcinoma [9].

Biological context of YTHDF1

• Amino acid sequence analysis showed that the peptide comprising residues 273-307 was labelled by both DACA and DACI [10].
• We infer from these findings that the side chains of DACA, its phenazine homologue, and 9-amino-DACA make comparable interactions with the DNA base pairs [11].
• Amsacrine, menadione, and 7-hydroxy-DACA were potent inhibitors of DACA metabolism in all three species, but 10-fold differences in IC50 values were apparent between species [12].
• Although both DACA and TAS-103 show a preference for topo IIalpha in whole cells using the TARDIS assay, the formation of low levels of topo I or topo IIbeta cleavable complexes may still play a role in cell death [13].
• In cell-free assays employing supercoiled plasmid DNA, C1-DACA at 5 microM induced topoisomerase I-mediated DNA breakage, indicating cleavable complex formation (poisoning), and at 10 microM it inhibited relaxation of DNA, consistent with suppression (self-inhibition) of poisoning [14].

Anatomical context of YTHDF1

• Most of the 5-substituted derivatives and the 7-Ph compound were more cytotoxic than DACA, but were less effective against JLA and JLD cell lines than in the wild-type JLC, suggesting a mode of cytotoxicity largely mediated by effects on topoisomerase II [15].
• Complexes of DACA and related acridine and phenazinecarboxamides bearing an N,N-dimethylaminoethyl side chain dissociate from calf thymus DNA by a kinetic pathway involving four discernible steps in a manner similar to complexes of N-[(2-dimethylamino)ethyl]-9-aminoacridine-4-carboxamide (termed 9-amino-DACA) [11].
• In addition, SKF-525A was a potent inhibitor of the metabolism of DACA in rat cytosol but caused minimal inhibition in the guinea pig or human preparations [12].
• BACKGROUND: The incidence of saccular aneurysms in the distal anterior cerebral artery (DACA aneurysms), also called pericallosal or A2 aneurysms, has been estimated to be from 1.5 to 9.0% of all intracranial aneurysms in large series in the literature [5,10,12,18] [16].

Associations of YTHDF1 with chemical compounds

• DACA lacks the anilino motif of the other three drugs but retains the acridine ring motif [7].
• With the fourth acridine DACA, five mutations were selected for resistance (betaG465D, betaH514Y, betaG550R, betaA596T, and betaD661N). betaG465D was selected with both DACA and mAMSA, and betaG550R, betaA596T, and betaD661N were selected with both DACA and AMCA [7].
• Amsacrine is a 9-anilinoacridine derivative that appears to act as an electron donor in ET reactions on DNA, while N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) may act as an electron acceptor [17].
• Overall, this new class of compounds appear to be mixed topo I/II inhibitors, up to 3-fold more cytotoxic than DACA in the human leukemia cell lines studied, with in vivo activity in colon 38 comparable to that of DACA and doxorubicin [18].
• The quinoline analogues showed cytotoxicities broadly similar to those of the known tricyclic acridine-4-carboxamide mixed topoI/II inhibitor DACA, with thieno and indeno analogues being the most active [18].

Analytical, diagnostic and therapeutic context of YTHDF1

• After incubations with DACA (range, 0-200 microM), DACA-9(10H)-acridone formation was determined by HPLC analysis [12].
• In this phase I study, DACA was given as a 3-h intravenous infusion on 3 successive days, repeated every 3 weeks [5].
• N-[(2'-Dimethylamino)ethyl]acridine-4-carboxamide (DACA) is a new anticancer agent currently undergoing clinical trials [12].
• Aliquots were analysed for DACA and its metabolites by high-performance liquid chromatography (HPLC) [19].
• N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide (DACA) is an experimental antitumour agent that has just completed phase I clinical trials in New Zealand and the United Kingdom [19].

References