Interaction of sodium salt of 9-oxo-10-acridineacetic acid (CMA) and its analogs with serum albumin. A model for study on binding of the interferon inducer with receptor.

Equilibrium dialysis, gel filtration and SDS polyacrylamide gel electrophoresis were used to study the interaction of sodium salt of 9-oxo-10-acridineacetic acid (CMA) as well as its analogs 7, 8, 11, 13 - 16 with proteins. The compounds were found to bind mainly to serum albumins. Several other proteins had no affinity to the compounds. The close analogs 7 and 8 (sodium salt of 2,7-dibromo-9-oxo-10-acridineacetic acid and sodium salt of 9-oxo-10-acridinebutyric acid) which were inactive as interferon inducers were found to have greater affinity to bovine, mouse or human albumin than the active IFN inducer--CMA. The mechanism of interaction of CMA as well as its close analogs with albumin resembled the first phase of reaction of pharmacologically active ligands with their specific receptor or acceptor proteins. CMA and some of its close analogs were also shown to stabilize the human erythrocyte membrane against hemolysis in the hypotonic solution. However, the activity of the compounds was much weaker than that of other so called membrane active drugs.

Phase I clinical and pharmacological study of 4'-(9-acridinylamino)-methanesulfon-m-anisidide using an intermittent biweekly schedule.

4'-(9-Acridinylamino)methanesulfon-m-anisidide (m-AMSA, NSC 249992), an acridine derivative, was given to 28 patients with solid tumors and one patient with Hodgkin's disease in a Phase I clinical trial. The dose schedule used was a single dose given every 14 days for three doses. The amount given ranged from 10 to 120 mg/sq m/dose. Dose-limiting toxicity was moderate to severe leukopenia which occurred at and above 70 mg/sq m. Thrombocytopenia was infrequent and did not require transfusion. Nonhematological side effects were mild and included nausea, vomiting, local irritation, and fever. Antineoplastic activity was noted in liposarcoma, adenocarcinoma of unknown primary origin, and squamous carcinoma of unknown primary origin (one patient each). Pharmacokinetics studies were done in 19 patients. Total m-AMSA and free m-AMSA concentrations showed a biphasic distribution with an initial rapid phase of t1/2 = 10 to 15 min for both, and a second slow phase of t1/2 = 8 to 9 hr for total m-AMSA and 3 hr for free m-AMSA. Phase II studies with m-AMSA, in hematological cancers are warranted, since its most consistent effect is on leukocytes. The recommended dosages for solid-tumor Phase II studies are 70 mg/sq m for good-risk patients and 50 mg/sq m for poor-risk patients, given as a single dose every other week, or 120 mg/sq m for poor-risk patients for the single-dose every-3-week schedule.

Further absorption studies with the anti-diarrhoeal agent ethacridine lactate in the dog.

2-Ethoxy-6,9-diaminoacridine lactate (ethacridine lactate, Rivanol, Metifex) has been administered orally to the dog once daily for 14 days, tritium labelled matterial having been given on days 1 and 14. The extent and rates of urinary excretion of radioactivity and the peak plasma levels and total radioactivity half-lives following the radiolabelled doses on days 1 and 14 were essentially the same. There was no significant change following multiple dosing in the level of urinary acridine-like material as determined fluorimetrically, which compared to approximately 0.01% of the dose found in the 0--24 h urine. It was concluded that, following oral administration of 3H-ethacridine lactate (5 mg/kg), less than 0.1% of the dose is absorbed as acridine-like material. Multiple dosing for 14 days does not alter this very low degree of oral absorption. In a separate study tritiated ethacridine lactate (30 microgram/kg) was administered i.v. to the dog. Approximately 84% of the radioactivity was eliminated in the 0--72 h post dose period, the majority of it being excreted via the faeces. There was a rapid loss of radioactivity from the plasma, followed by a long terminal phase in which acridine-like material was estimated to have a half-life of about 15 h.

The pharmacologic disposition of 4'-(9-acridinylamino)methanesulfon-m-anisidide in mice and rats.

The pharmacologic disposition of 4'-(9-acridinylamino)methanesulfon-m-anisidide (AMSA; NSC-141549), a new antitumor agent presently under consideration for phase I evaluation in man, was studied in mice and rats with 14C-AMSA labeled in the 9-carbon of the acridine ring. Radioactivity was selectively localized in the liver where it was present mainly as metabolites of AMSA. After 2 hr, nearly 50% of the plasma radioactivity was bound to protein and did not dissociate upon Sephadex G-200 chromatography. Radioactivity was rapidly eliminated in the bile; greater than 50% of the administered dose was excreted by this route in 2 hr. Bile/plasma ratios of greater than 400:1 indicated an active transport mechanism. The biliary transport mechanism was saturable with therapeutic doses. AMSA was found to be especially vulnerable to nucleophilic attack by alkylthiols resulting in displacement of 4-amino-3-methoxymethanesulfonanilide and the formation of the corresponding 9-alkylthioether of acridine. The major radioactive biliary metabolite (accounting for 90-95% of the biliary radioactivity) possessed the same chromatographic properties as the thiolysis product of AMSA and glutathione (GSH). A 40% reduction in liver GSH and a 20% reduction of liver GSH-transferase activity occurred after AMSA administration to mice. The pharmacologic disposition of AMSA can best be explained by a nonenzymatic nucleophilic attack on the 9-carbon atom of AMSA by endogenous thiols, resulting in the formation of 9-thioethers of acridine. Such an attack by low molecular weight thiols results in a product that is eliminated in urine and bile, whereas interaction with protein-thiol groups results in prolonged retention of the acridine moiety.