Antitumor Activity, Pharmacology, and Toxicity of Ellipticines, Ellipticinium, and 9-Hydroxy Derivatives: Preliminary Clinical Trials of 2-Methyl-9-Hydroxy Ellipticinium (NSC 264-137)

Paoletti, Claude; Pecq, J.‐B. Le; Dat-Xuong, N; Juret, P; Garnier, Hugues; Amiel, J. L.; Rouëssé, Jacques

doi:10.1007/978-3-642-81488-4_15

Cited by 132 publications

(56 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Celiptium R or N2-methyl-9-hydroxy-ellipticinium acetate (NMHE) is an antitumor drug in the ellipticine series, particularly used against osseous metastases of breast cancer (Paoletti et al 1980;Juret et al 1982). Celiptium is neither myelotoxic, nor hepatotoxic but induces nephrotoxicity in the Wistar rat (Raguenez-Viotte et al 1988).…”

Section: Introductionmentioning

confidence: 99%

Subcellular localization of celiptium-induced peroxidative damage in rat renal cortex

1991

View full text Add to dashboard Cite

Celiptium (N2-methyl-9-hydroxyellipticinium) is an antitumor agent of the ellipticine series. We have shown a dose-dependent nephrotoxicity in rats and demonstrated a lipid overload in proximal tubular cells (unsaturated free fatty acid accumulation). We have also shown an increase in thiobarbituric acid reactive substances (TBARS), namely the 4-hydroxyalkenals, that is paralleled by a decrease in phosphatidylethanolamine in rat kidney cortex. In the present study, peroxidative damage was localized in mitochondria, microsomal and brush-border membranes of kidney cortex. Female Wistar rats were injected with a single i.v. dose of 20 mg/kg celiptium and sacrificed on day 8. Subcellular fractionation studies showed that celiptium induced alterations: 1) in mitochondria (slight increase in aldehydes), 2) in microsomal membranes (increase in free fatty acids (FFA) with in particular rises in oleic (18:1) and linoleic (18:2) acids), 3) in brush-border membranes or BBM (decrease in protein and phospholipid contents); residual membranes showed an increase in oleic and linoleic acids and a decrease in the polyunsaturated fatty acids, arachidonic (20:4) and docosahexaenoic (22:6) acids, 4) in cytosol (increase in FFA and TBARS content). Thus, celiptium induces peroxidative damage in kidneys through lipid abnormalities which predominantly occur in brush-border membranes and consist of an increase in free fatty acids and aldehydes in cytosol.

show abstract

Section: Introductionmentioning

confidence: 99%

Subcellular localization of celiptium-induced peroxidative damage in rat renal cortex

1991

View full text Add to dashboard Cite

show abstract

“…The M+2 peaks were obtained by the fast atomic bombardment method. In desorption and chemical ionization, in both cases, the highest peak yielded mass 528 for 5 and 544 for 6 (the relative intensities of the main fragments are indicated in Fig. 2).…”

mentioning

confidence: 96%

Regioselective arylation of ribose in adenosine and guanosine with the antitumor drug N2-methyl-9-hydroxyellipticinium acetate.

Bernadou¹,

Meunier²,

Meunier³

et al. 1984

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The transformation of the antitumor drug N2-methyl-9-hydroxy-ellipticinium by a peroxidase-hydrogen peroxide system, which has been shown to occur in vivo, leads to an electrophilic quinone-imine derivative. This unstable molecule arylates in vitro purine nucleosides and nucdeotides, leading to regioselective adducts substituted ouly at the 2'-O position of the ribose, as shown by mass spectrometry and NMR. It is likely that an important preliminary step in this reaction is a stacking process between the ellipticinium ion and the purine rings, which might explain this regioselectivity.Ellipticine (1, 5,11-dimethyl-6H-pyrido[4,3b]carbazole) was first described as a natural antitumor alkaloid in 1967 (1).

show abstract

“…Elliptinium acetate is an anti-neoplastic agent derived from ellipticine which is currently used in the treatment of metastatic breast cancer (Paoletti et al, 1980;Auclair et al, 1987). The incorporation of the lipophilic derivative was performed by a technique which consisted of a fusion of micro emulsion containing drug with LDL (Samadi-Baboli et al, 1989).…”

mentioning

confidence: 99%

Low density lipoprotein for cytotoxic drug targeting: improved activity of elliptinium derivative against B16 melanoma in mice

Samadi-Baboli

Favre²,

Canal³

et al. 1993

Br J Cancer

View full text Add to dashboard Cite

Summary Significant low density lipoprotein (LDL) uptake by tumour cells led to the use of LDL as a discriminatory vehicle for the delivery of cytotoxic drugs. In the current study, the lipophilic elliptinium derivative, elliptinium-oleate (OL-NME), was incorporated into LDL to reach an incorporation level of 400 molecules per LDL particle. The OL-NME-LDL complex showed cytotoxic effects on normal human fibroblasts while the cytotoxicity was not observed on receptor-defective human fibroblasts, indicating the ability of the complex to be preferentially metabolised by the LDL receptor. In vivo metabolism of the complex was related to the LDL receptor pathway. The metabolic clearance was the same for native LDL (17.1 ml h-') and OL-NME-LDL complex (16.2 ml h'). LDL incorporated OL-NME enhanced the antitumour activity against murine B16 melanoma model; this resulted from increased efficacy for OL-NME-LDL at doses equal to free 9-OH-NME (157 vs 76 of Increase Life Span (ILS) (%) values after intraperitoneal (i.p.) drug injection on i.p. implanted tumour model and 45 vs -2 ILS (%) values after intravenous drug injection on subcutaneous implanted tumour model). These data suggest that LDL improves the potency of lipophilic cytotoxic drugs against tumours that express LDL receptor activity.

show abstract

Antitumor Activity, Pharmacology, and Toxicity of Ellipticines, Ellipticinium, and 9-Hydroxy Derivatives: Preliminary Clinical Trials of 2-Methyl-9-Hydroxy Ellipticinium (NSC 264-137)

Cited by 132 publications

References 21 publications

Subcellular localization of celiptium-induced peroxidative damage in rat renal cortex

Subcellular localization of celiptium-induced peroxidative damage in rat renal cortex

Regioselective arylation of ribose in adenosine and guanosine with the antitumor drug N2-methyl-9-hydroxyellipticinium acetate.

Low density lipoprotein for cytotoxic drug targeting: improved activity of elliptinium derivative against B16 melanoma in mice

Contact Info

Product

Resources

About