Metabolism and disposition studies of 9-hydroxyellipticine and 2-methyl-9-hydroxyellipticinium acetate in animals.

Radiolabeled 9-hydroxyellipticine (iv and ip routes) and the corresponding radioactive quaternary salt, 2-methyl-9-hydroxyellipticinium acetate (iv route), were administered to mice. Tissue distribution was then followed up to 64 hours by means of autoradiography. Both drugs accumulated in the kidneys, lungs, and liver; 9-hydroxyellipticine also accumulated in the spleen and bone marrow. The quaternary salt was concentrated in the gastrointestinal walls and the salivary and thyroid glands; none was found in the brain. Metabolic studies after administration of these antitumor drugs to rats and mice showed that 9-hydroxyellipticine is extensively metabolized, mainly to its glucuronide. Under our experimental conditions, the ellipticinium derivative was excreted unchanged in the bile (70%) and in the urine (30%). Pharmacokinetic studies in mice using either radioactivity measurements or selective extraction followed by spectrofluorometric quantitation have shown that blood levels drop very rapidly during the distribution phase followed by a much slower disposition phase, with a half-life of about 30 hours for the quaternary salt.

Antitumor activity, pharmacology, and toxicity of ellipticines, ellipticinium, and 9-hydroxy derivatives: preliminary clinical trials of 2-methyl-9-hydroxy ellipticinium (NSC 264-137).

Ellipticine and some derivatives are highly cytotoxic substances which kill L1210 cells at concentrations ranging form 10(-8) to 10(-6)M. Some compounds in this series bind with high affinity to DNA (affinity constant between 10(7) M-1 and 10(5) M-1) by intercalation between base pairs. The antitumoral properties of these derivatives are thought to be related to their DNA-binding ability. Both 9-hydroxylation of ellipticine and quaternarization of 2-pyridinic nitrogen tend to increase DNA binding and antitumor activity. 2-Methyl-9-hydroxyellipticine (NSC 264-137) was selected for a phase I and later for a phase II trial in human cancer. This drug does not affect blood cell counts in animals or in man. It is not mutagenic in the Ames' test nor teratogenic in mice, but is endowed with anti-inflammatory properties and induces a marked decrease of motoricity in mice. Transient bradycardia and decrease of blood pressure are the most noticeable cardiovascular effects in dogs. This compound administered at 80-100 mg/m2/week in 1-h intravenous (IV) infusion induces objective remissions in about 25% of patients suffering from advanced breast cancer refractory to all other treatment. These remissions, which occurred after 3-4 weeks, lasted for 1-18 months. This drug seems particularly to improve the condition of patients suffering from oesteolytic breast cancer metastasis. Activity against anaplastic thyroid carcinoma and ovarian carcinoma has also been observed in some cases. Toxic side effects are nausea and vomiting (one-third of the patients), hypertension (less than 10% of the patients), muscular cramp (one-third of the patients), fatigue which can be very pronounced (in most patients after 3 months of treatment), mouth dryness, and mycosis of the tongue and esophagus (less than 20% of the patients).

[Anti-inflammatory effect of hydroxy-9-ellipticine]. / Action anti-inflammatoire de l'hydroxy-9 ellipticine

The anti-inflammatory activity of 9-hydroxy-ellipticine is studied through various experimental models. It is particularly interesting in the guinea-pig cutaneous erythema, in the carragenin-induced oedema and in the adjuvant-induced polyarthritis in the rat. It appears in immune or non-immune induced inflammatory responses. Its important thymolytic activity can be related to its immunosuppressive effect.

[Trypanocidal activity of some ellipticine derivatives against Trypanosoma cruzi cultured in vitro]. / Activité trypanocide de quelques dérivés de l'ellipticine sur Trypanosoma cruzi cultivé in vitro

Some ellipticine derivatives showing antitumoral behaviour exhibit a trypanocide activity against in vitro cultures of T. cruzi. 9-Methoxy-6-methyl-ellipticine is the most active compound of this series: its lethal effect is comparable with that of ethidium bromide.

[Bacteriostatic and bacteriacidal activity of hydroxy-9 ellipticine in vitro]. / Hydroxy-9 ellipticine: activité bactériostatique et bactéricide in vitro

9-Hydroxy-ellipticine shows a clear effect against bacterial development. This effect depends essentially upon the bacterial species. Two groups can be differentiated: Group I with resisting species composed by negative Gram Bacilli (Enterobacteria and Pseudomonas); Group II with sensitive species formed by Coccus, positive Gram Bacilli, Mycobacterium tuberculosis and Anaerobes.