A Phase II Trial of Amonafide in Patients With Endometrial Cancer

Abstract

Twenty-nine evaluable patients with endometrial cancer were treated with amonafide 300 mg/m2 for 5 consecutive days every 3 weeks. Two partial responses (8%) were seen. Hematologic toxicity was severe or life-threatening in 13 patients occurring as follows: leukopenia in 13 patients (45%); thrombocytopenia in 10 patients (34%); granulocytopenia in 13 patients (45%); and anemia in four patients (14%). In view of the low response rate and high toxicity, this dose schedule of amonafide does not warrant further investigation in endometrial cancer.

Synthesis and Cytotoxic Activity of Carboxamide Derivatives of Benzo[b][1,6]naphthyridines

“…Compound 9, with the cationic side chain in place of the 1-oxo group of compounds 7, produced only a small growth delay at the highest tolerated dose. [1,6]naphthyridines are an interesting new class of antitumor agents, with some showing curative in vivo activity in the sc 38 model in a single dosing protocol. The range of 2-substituents that produce significant activity is apparently wide.…”

“…A slight anomaly occurred when ammonia was used instead of an alkylamine, since the product that separated from the reaction mixture in this case alone contained some ammonium species; a triplet at 7.1 ppm (broad or sharp with J ) 51 Hz, depending on solvent and conditions) was evident in the 1 H NMR spectrum, though the NH (δ 12.2) and CO 2 H (δ 16.0) proton singlets could also be seen. Liberation of 6c required treatment of this material with acid (this turned out to be important to avoid complications in further reac- tions).…”

“…N2-and carbon-substituted derivatives of the benzo-[b] [1,6]naphthyridin-2(1H)-one system are known. [7][8][9][10] Dibenzo[b,h] [1,6]naphthyridin-6(5H)-ones have also been reported, 7,11 but the synthetic route in the present work differs from these previous examples.…”

“…A number of compounds comprising tricyclic chromophores bearing a flexible cationic side chain are known to show cytotoxic effects. These include benzisoquinolinediones (e.g., amonafide, 1 , ), anthraquinones (e.g., mitoxantrone, 2 ), and acridine-4-carboxamides (e.g., DACA, 3 , ). Their utility as anticancer drugs is considered to be primarily through their ability to inhibit topoisomerase enzymes.…”

“…4 We recently reinvestigated the reaction of homophthalic acid derivatives with Vilsmeier reagent and extended this to formation of quinoline analogues 5. 6 We have now found that 5 reacts readily with a range of primary amines to form 2-substituted 1-oxo-1,2dihydrobenzo[b] [1,6]naphthyridine-4-carboxylic acids 6 (Scheme 1). Subsequently, new carboxamides 7 derived from these were obtained, where the peri arrangement of amide and central ring nitrogen seen in DACA is duplicated.…”