A new antitumor agent: methyl sulfonium perchlorate of echinomycin.

Newly modified-echinomycin such as S-methylated sulfonium perchlorate of echinomycin (1), monosulfoxide (2), disulfoxid (3) and sulfone (4) have been prepared and evaluated for in vitro biological activities of cytotoxicity against P388, B16 and SNU-16 as well as in vivo antitumor activity against murine leukemia P388 and melanoma B16.

Echinomycin (NSC 526417) in advanced ovarian cancer. A phase II trial of the Gynecologic Oncology Group.

Twenty-two patients with recurrent carcinoma of the ovary progressive after initial chemotherapy (21 with cisplatin-based treatment) were entered on a phase II trial utilizing Echinomycin at a dosage of 1,500 micrograms/m2 every 4 weeks. There were two complete responders and no partial responders (9% response, 95% confidence intervals for complete and partial responses of 1-29%). Major toxicity was modest and consisted mainly of nausea and vomiting. Echinomycin displays minimal activity as salvage therapy in women with advanced ovarian cancer at this dose and schedule.

Phase I trial of echinomycin (NSC 526417), a bifunctional intercalating agent, administered by 24-hour continuous infusion.

Echinomycin was administered to 43 patients with advanced cancer in escalating doses ranging from 60 to 2128 mcg/m2. The dose-limiting toxicity of echinomycin administered as a 24-h continuous infusion every 28 days was nausea and vomiting beginning at the end of the 24 h infusion and lasting from 3 to 8 days. Other toxicities included sporadic thrombocytopenia and biochemical evidence of liver dysfunction characterized by elevations in SGOT. Peripheral vein phlebitis was noted in 100% of patients, and watery diarrhea of 24-48-h duration was noted in 7% of patients. The maximally tolerated dose of echinomycin was 2128 mcg/m2. The recommended dose for phase II trials utilizing the 24-h continuous infusion schedule is 1600 mcg/m2 repeated every 28 days with pretreatment antiemetics.

Echinomycin: the first bifunctional intercalating agent in clinical trials.

Echinomycin is a quinoxaline antibiotic that was originally isolated from Streptomyces echinatus. Based on its antitumor activity against two i.p. implanted murine tumors, the B16 melanoma, and the P388 leukemia, it was brought into clinical trials by the National Cancer Institute. Recent studies on its cytotoxic action have related its antitumor activity with its ability to bifunctionally intercalate with double stranded DNA. Toxicologic studies were carried out in CDF1 mice and beagle dogs using intravenous injections. For the mice studies the dose ranges were 288-692 mcg/kg (864-2076 mcg/m2) by single bolus, and 112-254 mcg/kg/day (336-762 mcg/m2/day) for five consecutive days. In the dog, dose ranges studied were 8.9-89.4 mcg/kg (178-1788 mcg/m2) by single bolus, and 3.4-33.5 mcg/kg/day (68-670 mcg/m2/day) for five consecutive days. The major toxic effects were found in the gastrointestinal, hepatic, and lymphoreticular systems. These were reversible at all but the highest dose, in dogs that had been treated for five consecutive days. Phase I clinical trials using various intravenous schedules were sponsored by the National Cancer Institute. Nausea, vomiting, reversible liver enzyme abnormalities, and allergic reactions were the most common toxicities encountered. Based on results from these studies, the National Cancer Institute has recently begun phase II trials in a broad range of diseases. These trials will further characterize echinomycin's toxic effects and its antitumor activity.

Directed biosynthesis of novel derivatives of echinomycin by Streptomyces echinatus. I. Effect of exogenous analogues of quinoxaline-2-carboxylic acid on the fermentation.

Streptomyces echinatus A8331 cultured on a maltose minimal salts medium normally produces a single antibiotic, echinomycin (quinomycin A), containing two quinoxaline-2-carbonyl chromophores. Echinomycin is powerfully active against experimental tumours and can be assayed by its activity against Gram-positive bacteria. Grown in the presence of aromatic carboxylic acids related to quinoxaline, S. echinatus responds in favourable circumstances by incorporating the added material into analogues of the natural antibiotic having replacement chromophores. Both mono- and bis-substituted derivatives are formed. With quinoline-2-carboxylic acid as precursor, large quantities of analogues are produced, and the time course of synthesis, extraction, purification, assay, and characterization of the derivatives are described. Twenty-two other aromatic acids have been tested as potential substrates for antibiotic analogue biosynthesis. Half of them did not significantly affect growth and echinomycin production. Five appeared to stimulate antibiotic synthesis, while the remainder proved inhibitory. New biologically active antibiotics were detected in cultures supplemented with 7-chloroquinoxaline-2-carboxylic acid; 1,2,4-benzo-as-triazine-3-carboxylic acid; thieno[3,2-b]pyridine-5-carboxylic acid; and 6-methylquinoline-2-carboxylic acid.

Cytotoxic activity of echinomycin in a human tumor cloning system.

A human tumor cloning system was utilized to screen for in vitro antitumor effects of the investigational anticancer agent Echinomycin. Tumors from 562 patients (24 different histological tumor types) were placed in culture. Two hundred fifty-five specimens were evaluable for drug sensitivity information (i.e., greater than or equal to 20 colonies in control plates). The overall in vitro response rates (defined as less than 50% survival of tumor colony-forming units) at three different doses of Echinomycin (0.001, 0.01, and 0.1 micrograms/ml) were between 16% and 19%. Echinomycin showed minor in vitro cytotoxic activity in breast and colon cancer, and in sarcoma. A comparison of these in vitro results with the results of phase-II clinical trials, as they become available, will help to evaluate the utility of the human tumor cloning system for predicting clinical antitumor activity of new antineoplastics.

[Study of the toxicity and antiblastoma activity of antibiotics echinomycin and 6270 in complexes with DNA]. / Izuchenie toksichnosti i antiblastomnoi aktivnosti antibiotikov ékhinomitsina i 6270 v kompleksakh s DNK.

Studies with the use of intact inbred albino mice showed that in intravenous administration the acute toxicity of antibiotic No. 6270 and echinomycin in complexes with DNA increased 3--4 times as compared to the toxicity of the same antibiotics used without the complex. Under the experimental conditions with 3-fold intravenous administration at 72-hour intervals in doses equivalent by their acute toxicity, the antitumor activity of the echinomycin complex with DNA against the solid form of lymphosarcoma L10-1 was approximately 4 times lower than the activity of the antibiotic used alone. Like echinomycin, antibiotic No. 6270 in complex with DNA used according to the same administration scheme in doses equivalent by their acute toxicity had a lower inhibitory effect on growth of lymphosarcoma L10-1 and sarcoma 180 as compared to its use alone.