Summary
Datelliptium chloride, hydrochloride (SR 95 156B, NSC 626718X, DHE) was studied in a phase I trial of escalating doses given on a single 24-h continuous intravenous infusion schedule. Doses were escalated from 40 to 500 mg/m2 in 19 patients who received a total of 24 courses. Courses were repeated after a minimal interval of 3 weeks. Local venous toxicity occurred at low doses (≤100 mg/m2) and was circumvented by the use of a central venous access for higher doses. Other clinical adverse events occurred (≥330 mg/m2), including moderate nausea and vomiting, mild diarrhea, dry mouth, neuropsychiatric manifestations, and fatigue. All of these side effects were reversible and none was dose-limiting. The dose-limiting toxicity was related to hepatic laboratory-test abnormalities in the form of reversible elevations of levels of serum bilirubin and liver enzymes at doses of ≥330 mg/m2. The maximum tolerated dose for this schedule is 500 mg/m2. Hematologic toxicity was minimal and non-dose-limiting. Neither drug-related deaths nor objective complete or partial responses were observed. However, a minor response and a long-term disease stabilization were obtained.
References
Auclair C, Pierre A, Voisin E, et al (1987) Physicochemical and pharmacological properties of the antitumor ellipticine derivative 2-(diethylamino-2-ethyl) 9-hydroxy ellipticinium chloride, HCl. Cancer Res 47:6254–6261
Buzdar AU, Hortobagyi GN, Espanza LT, et al (1990) Elliptinium acetate in metastatic breast cancer — a phase II study. Oncology 47: 101–104
Fellous R, Berger Y, Gouyette A (1989) Pharmacokinetic, disposition, and metabolic studies of 2-(diethylamino-2-ethyl)-9-hydroxy ellipticinium chloride in rats. Proc Am Assoc Cancer Res 30:537
Le Pecq JB, Dat-Xuong N, Gosse C, Paoletti C (1974) A new antitumoral agent: 9-hydroxy ellipticine. Possibility of a rational design of anticancerous drugs in the series of DNA intercalating drugs. Proc Natl Acad Sci USA 71:5078–5082
Miller AB, Hoogstraten B, Staquet M, Winkler A (1981) Reporting results of cancer treatment. Cancer 47:207–214
Mondesir JM, Bidart JM, Goodman A, et al (1985) Drug-induced antibodies during 2-N-methyl-9-hydroxyellipticinium acetate (NSC-264 137) treatment: schedule dependency and relationship to hemolysis. J Clin Oncol 3:735–740
Multon E, Riou JF, Lefevre D, Ahomadegbe JC, Riou G (1989) Topoisomerase II-mediated DNA cleavage activity induced by ellipticine in the human tumor cell line N 417. Biochem Pharmacol 38: 2077–2086
Piccart M, Dodion P, Merle S, Sculier JP, Crespeigne N, Wery F (1989) Phase I trial with 9-OH-2-N-diethylaminoethyl ellipticinium chloride, hydrochloride (SR 95156B). Invest New Drugs 7:457
Pierson V, Pierre A, Pommier Y, Gros P (1988) Production of protein-associated DNA breaks by 10-diethylaminopropyl-amino-6-methyl-5H-pyrido[3′, 4′:4, 5]pyrrolo-[2, 3-g]-isoquinoline (BD 40) in cultured L1210 cells and in isolated nuclei. Comparison with other topoisomerase II inhibitors. Cancer Res 48:1404–1409
Pommier Y, Minford JK, Schwarts RE, Zwelling LA, Kohn KW (1985) Effects of the DNA intercalators 4′-(9-acridinylamino)methanesulfon-m-anisidide and 2-methyl-9-hydroxy ellipticinium on topoisomerase II-mediated DNA strand cleavage and strand passage. Biochemistry 24:6410–6416
Rouessé J, Huertas D, Sancho-Garnier H, et al (1981) 2-N-methyl-9-hydroxy ellipticine in treatment of metastatic breast cancer. Bull Cancer (Paris) 68:437–441
Svoboda GH, Poore GA, Montfort ML (1968) Alkaloids ofOchrosia maculata Jacq. (Ochrosia borbanica Gmel.): isolation of the alkaloids and study of the antitumor properties of 9-methoxy ellipticine. J Pharm Sci 57:1720–1725
Treat J, Greenspan A, Rahman A, McCabe MS, Byrne PJ (1989) Elliptinium: phase II study in advanced measurable breast cancer. Invest New Drugs 7:231–234
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Khayat, D., Borel, C., Azab, M. et al. Phase I study of Datelliptium chloride, hydrochloride given by 24-h continuous intravenous infusion. Cancer Chemother. Pharmacol. 30, 226–228 (1992). https://doi.org/10.1007/BF00686318
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DOI: https://doi.org/10.1007/BF00686318