Drug-induced antibodies during 2-N-methyl-9-hydroxyellipticinium acetate (NSC-264137) treatment: schedule dependency and relationship to hemolysis.

Drug-dependent antibodies were investigated in patients treated with elliptinium acetate, a cytostatic drug with activity in advanced breast cancer. Retrospective analysis of 83 patients, receiving weekly intravenous elliptinium, showed a high incidence of anti-elliptinium antibodies (20%). Hemolysis occurred among antibody-positive patients, apparently related to the antibody titer. The predictability of anti-elliptinium antibodies for hemolysis and the schedule dependency of antibody development was examined prospectively. Among 42 patients treated weekly for at least three courses, 40% developed antibodies. Of 30 patients receiving elliptinium daily for three days every three weeks, none developed either antibodies or hemolysis. Only antibody positive patients, with titers greater than or equal to 32 were at risk for hemolysis. The possible mechanisms are discussed.

Phase II study of elliptinium acetate salvage treatment of advanced breast cancer.

Elliptinium acetate (Celiptium) is an intercalating agent belonging to the ellipticine family. This agent has demonstrated clinical activity as salvage treatment in breast cancer using a weekly regimen. However, its clinical use was hampered by important toxicities such as xerostomia and immune-mediated haemolytic reactions due to development of anti-elliptinium IgM antibodies. We have studied 83 patients previously treated for metastatic breast cancer using elliptinium acetate with a different schedule: 80 mg/m2 daily for 3 consecutive days every 21 days. In 80 evaluable patients, an objective response (complete + partial response) was obtained in 5 of 30 patients with visceral metastases (13%), in 6 of 21 patients with soft tissue metastases (29%), and in 3 of 20 patients with mixed metastases (15%). The overall objective response rate was 14/80 (18%, 95% confidence interval = 10-26%). Moderate to severe xerostomia occurred in 10% of patients, while no anti-elliptinium antibodies or haemolytic reactions were detected using this schedule. No significant haematological toxicity, as usually reported with this drug, was observed. Elliptinium acetate has modest but definite activity as salvage treatment of breast cancer. The 3-week schedule seems as active as and less toxic than the weekly schedule.

Phase I study of Datelliptium chloride, hydrochloride given by 24-h continuous intravenous infusion.

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 (less than or equal to 100 mg/m2) and was circumvented by the use of a central venous access for higher doses. Other clinical adverse events occurred (greater than or equal to 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 greater than or equal to 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.

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).

Phase II trial of elliptinium in advanced renal cell carcinoma and carcinoma of the breast.

Elliptinium, 100 mg/m2 i.v. weekly, was administered to 14 patients with advanced renal cancer and 4 with breast cancer. There were no responses in 11 adequately treated patients. An unexpectedly high incidence of xerostomia, allergic, and hemolytic reactions were observed, which resulted in cessation of the trial. Recent data suggest polymer formation occurs with reconstituted elliptinium, and further trials are warranted when a new formulation is available.

[Hydroxy-9-methyl-2-ellipticinium (NSC 264-137) for osseous metastases from breast cancer. A 4 year experience (author's transl)]. / L'hydroxy-9-methyl-2-ellipticinium (NSC 264-137) dans le traitement des métastases osseuses du cancer du sein. Bilan d'une expérimentation de 4 années.

In 96 patients (95 women--1 man) with osseous metastases from breast cancer suitable for analysis an objective remission was obtained with hydroxy-9-methyl-2-ellipticinium (100 mg/m2 weekly) in 31 cases. These responses lasted from 3 to 17 months. The main characteristic of this compound is its lack of marrow toxicity, a property of value in osseous lesions where marrow is so frequently involved, making difficult the use of conventional chemical drugs. The principal unpleasant drawback is an inhibition of the salivary secretion which causes other side effects such as tongue mycosis, anorexia, and asthenia. Less frequently immunologic disorders and a few cases of renal insufficiency were observed.

[Failure of elliptinium acetate in the treatment of unresectable hepatocarcinoma (phase II trial)]. / Echic de l'acetate d'elliptinium dans le traitement de l'hepatocarcinome inopérable (essai phase II).

Fifteen patients with hepatocellular carcinoma were administered elliptinium acetate in a phase II trial. A dose of 80 mg/m2/day was administered during 3 consecutive days, every 3 weeks. According to WHO criteria regarding response, no objective responses were observed. The major toxicity was dryness of the mouth which occurred in 73% of patients, on addition, one case of hemolysis was documented in spite of a systematic search for anti-elliptinium antibodies prior to each injection. In conclusion, elliptinium acetate has no valuable therapeutic impact on the treatment of hepatocellular carcinoma.

[2 N methyl 9 hydroxy-ellipticine in treatment of metastatic breast cancers (author's transl)]. / Intérêt de la 2 N-methy-9-hydroxy-ellipticine (NSC 264-137) dans le traitement des cancers du sein métastasés.

A phase II trial was conducted in 57 patients with advanced metastatic breast cancer given 2-N-methyl 9-hydroxy-ellipticine (NMHE) as 100 mg/m2 weekly. Evaluation of response, after at least 4 injections, was possible in 46 patients. Two complete regressions (of 3 and 12 months) and 7 regressions of over 50 p. cent were observed, a total regression rate of 19 p. cent. Regression was mainly observed in cutaneous or subcutaneous metastases. No objective regression was noted for pulmonary or hepatic metastases. Bone metastases were not taken in account when assessing response to treatment. Absence of haematological changes must be emphasized. The most frequent side effects were anorexia, nausea +/- vomiting and dryness of mouth. Major toxicity was intravascular haemolysis, observed in 6 of 175 patients receiving NMHE in the Institut Gustave-Roussy, always controlled by symptomatic treatment. This product, of acceptable efficacy in breast cancer treatment, will probably occupy an original place in anti-cancer chemotherapy because of its lack of myelotoxicity.

Polyclonal antibodies to elliptinium acetate: structure-activity relationships and comparison with human anti-elliptinium IgM.

In order to elucidate the immune-mediated hemolytic disease induced in man by elliptinium acetate, a quaternary ammonium compound with antineoplastic activity, polyclonal antibodies directed against this hapten were raised in rabbits. The coupling step between drug and carrier was performed according to a putative human in vivo hapten conjugation mechanism. Structure-activity relationships of the resulting IgG were compared with the epitope site recognized by human anti-elliptinium IgM by using a panel of twelve elliptinium acetate analogues. Although both antibodies were directed principally against the quaternary ammonium ion, a poor correlation between the cross-reactivity indices was obtained. In fact, it appeared that both antibodies recognized specifically the ammonium group plus different regions of the molecule: the indole ring for human antibodies, the N-alkyl group and its vicinity for rabbit ones. The specificity of the obtained rabbit polyclonal antisera is discussed, with regard to the conjugation mechanism of the drug occurring in man.

Drug dependent red cell antibodies and intravascular haemolysis occurring in patients treated with 9 hydroxy-methyl-ellipticinium.

Eleven patients were treated weekly with a new cytostatic drug, 9-hydroxy-methyl-ellipticinium (9 HME). Eight were treated for longer than 4 weeks and three of these developed a drug dependent antibody reacting with normal red cells. In two of these patients acute intravascular haemolysis occurred, one with oliguric renal failure; in the third patient the drug was stopped as soon as the antibody was detected. In all three patients the antibody developed after 4 weeks of treatment. It was IgM, agglutinated normal red cells and bound complement only in the presence of the drug. No antibodies could be detected in the patient's serum reacting with normal platelets in the presence of the drug. The incidence of haemolysis with this drug is much higher than seen with other drugs causing immune-complex haemolysis. Studies done with closely related substances suggest that the antigenic site of the drug is related to the group attached to carbon atom 9.

Phase I study of elliptinium (2-N-methyl-9-hydroxyellipticinium).

Elliptinium (2-N-methyl-9-hydroxyellipticinium), a chemotherapeutic agent whose mechanism of action has not been completely elucidated, intercalates into DNA. In this Phase I clinical trial, the schedule of drug administration consisted of weekly intravenous infusions. Twenty-nine patients were evaluable for toxicity. The initial dose level was 40 mg/m2 and was escalated to 150 mg/m2 through six levels. The dose-limiting side effects were emesis, xerostomia, and azotemia. The lack of myelosuppression was the most striking feature. Objective responses (partial remission, minor response) were seen in one patient each with Hodgkin's disease, non-Hodgkin's lymphoma, breast cancer, and nasopharyngeal carcinoma. We recommend a Phase II evaluation of elliptinium at a dose of 100 mg/m2 on a weekly schedule.

Elliptinium acetate in metastatic breast cancer--a phase II study.

Thirty-five patients with metastatic breast cancer who had received one or two prior chemotherapeutic regimens were treated with elliptinium acetate at a dose of 80 mg/m2 for 3 days every 3 weeks. Of the 33 patients evaluable for response, 1 patient achieved complete remission, 4 achieved partial responses (15% overall objective response with 95% confidence interval of 5-32%), and 6 achieved minor response. Toxicity of the treatment was xerostomia, diarrhea, and nausea and vomiting. The drug was not myelosuppressive. Three patients showed evidence of elliptinium antibody, and treatment was discontinued. No episodes of hemolysis were observed. Elliptinium acetate showed modest antitumor activity in previously treated patients with metastatic breast cancer.

[Hydroxy 9-methyl 2-ellipticinium acetate (NSC 264-137). Toxicologic study and therapeutic effect in 100 cancers (author's transl)]. / L'acétate d'hydroxy 9-méthyl 2-ellipticinium (NSC 264-137). Etude toxicologique et thérapeutique chez 100 cancéreux.

A new derivative of ellipticine, hydroxy-9-methyl-2-ellipticinium acetate, was found to be a useful anti-tumor drug in advanced cancers which could not be treated any longer successfully by any other procedure. In our series of 100 patients, the best results were obtained with bone metastases from breast carcinomas and with anaplastic thyroid carcinomas. Most patients usually received a weekly perfusion of 80 mg/m2. The main characteristic of this drug is its lack of hematologic, and hepatic toxicity. No renal trouble was observed during the first year, but 2 deaths from renal insufficiency occured during the 18th and 15th month of treatment. The most frequent side effect consists of digestive troubles (nausea, vomiting) which rarely compelled to stop the treatment (4 times in 100 patients).

2-Methyl-9-hydroxyellipticinium acetate (ellipticinium) in the treatment of lymphomas. Preliminary results of a phase II study.

Eighteen patients with advanced refractory lymphomas were treated with 2-methyl-hydroxyellipticinium (ellipticinium); there were 14 non-Hodgkin's (NHL) and 4 Hodgkin's lymphomas (HL). Ellipticinium was administered at the dose of 100 mg/m2 daily for 3 days i.v. with courses repeated at 3 week intervals. Preliminary results indicate some antitumor activity of the drug against NHL with minimal toxicity. Of the 16 evaluable patients 1 partial remission and 7 minor responses were noted among the NHL (65%). Myelosuppression was minimal and clinical toxicity was mild. Further evaluation of this drug in untreated patients appears to be warranted.

Elliptinium: phase II study in advanced measurable breast cancer.

Eighteen patients with advanced measurable breast cancer were treated with elliptinium acetate 100 mg/m2 x 3 days every 3 weeks. Fourteen of these patients had failed prior chemotherapy. Two patients had an objective tumor response of greater than 4 weeks. Myelosuppression, renal insufficiency and thrombophlebitis were rarely encountered and alopecia was not seen at all. This study demonstrates that elliptinium has minimal activity in recurrent breast cancer with a favorable toxicity profile.

[N-Methyl-9 hydroxy-ellipticine (NSC 264-137) in the treatment of malignant metastases. Preliminary results (author's transl)]. / Intérêt de la 2 N-méthyl-9 hydroxy-ellipticine (NSC 264-137) dans le traitement des cancers métastasés. Résultat d'une étude préliminaire.

In a phase II trial 2 N-Methyl-9-Hydroxy-Ellipticine (NMHE) was administered in weekly infusions of 100mg/m2 over 1 hour to patients with malignant metastases. Prior to injection, the drug was dissolved in 250 ml isotonic glucose. The results were evaluated in 67 patients. Objective regression was observed in 23 (34%) and was superior to 50% in 10 cases. Patients showing signs of regression under treatment were mostly those with breast cancer (10/24 cases), soft tissue sarcoma (3/9 cases) and renal cancer (2/8 cases). The main toxic effect was haemolysis (2 cases), probably due to an immunoallergic mechanism. Attention is drawn to the lack of bone marrow toxicity.

[Renal toxicity of 9-hydroxy-2-methyl-ellipticinium]. / Toxicité rénale du 9-hydroxy-2-méthylellipticinium.

9-hydroxy-2-methyl-ellipticinium (HME) is an intercaling agent mainly potent in metastatic breast cancer. Its almost complete lack of bone marrow toxicity is of greatest value. However, among 385 patients 20 cases of renal failure were observed: renal failure is gradual, non reversible except in four cases with acute renal failure. Histological and ultrastructural studies, performed in 8 cases, showed exclusively proximal tubular lesions, without glomerular or interstitial lesions. We have evidence that there is a relation between the cumulative dose and the severity of the lesions. A prospective study was done in 30 patients. An increase in enzymuria, proteinuria and glycosuria was observed in most patients after HME infusion. HME is an efficient drug in the treatment of bone metastases of breast cancer. Renal function should be carefully monitored during HME administration.

Phase II trial of elliptinium in advanced renal cell carcinoma.

Forty patients with advanced renal cell carcinoma were treated with elliptinium by a weekly infusion of 100 mg/m2. Of 38 evaluable patients, five had an objective response (13.2%). Average response duration was 8 months (range, 5-11). The major dose-limiting toxic effect was induction of antielliptinium antibodies, with the risk of intravascular hemolysis. Elliptinium has modest activity in advanced renal cell cancer and does not produce myelosuppression.