RESUMEN
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.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Elipticinas/uso terapéutico , Sustancias Intercalantes/uso terapéutico , Adulto , Anciano , Elipticinas/efectos adversos , Femenino , Humanos , Persona de Mediana Edad , Estudios Prospectivos , Terapia Recuperativa , Xerostomía/inducido químicamenteRESUMEN
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.
Asunto(s)
Antineoplásicos/uso terapéutico , Elipticinas/uso terapéutico , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Evaluación de Medicamentos , Elipticinas/administración & dosificación , Elipticinas/efectos adversos , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana EdadRESUMEN
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.
Asunto(s)
Alcaloides/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Elipticinas/uso terapéutico , Adulto , Anciano , Antineoplásicos/efectos adversos , Evaluación de Medicamentos , Elipticinas/efectos adversos , Femenino , Humanos , Persona de Mediana Edad , Metástasis de la NeoplasiaRESUMEN
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.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Alcaloides/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Elipticinas/uso terapéutico , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Evaluación de Medicamentos , Elipticinas/administración & dosificación , Elipticinas/efectos adversos , Femenino , Humanos , Persona de Mediana Edad , Metástasis de la NeoplasiaRESUMEN
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.
Asunto(s)
Alcaloides/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Elipticinas/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Anciano , Antineoplásicos/efectos adversos , Ensayos Clínicos como Asunto , Elipticinas/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
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.
Asunto(s)
Alcaloides/inmunología , Elipticinas/inmunología , Anemia Hemolítica/inducido químicamente , Anemia Hemolítica/inmunología , Animales , Reacciones Cruzadas , Elipticinas/efectos adversos , Humanos , Inmunoglobulina G/inmunología , Inmunoglobulina M/inmunología , Conejos , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Alcaloides/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Elipticinas/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Anciano , Antineoplásicos/efectos adversos , Evaluación de Medicamentos , Hipersensibilidad a las Drogas/etiología , Elipticinas/efectos adversos , Femenino , Hemólisis , Humanos , Masculino , Persona de Mediana Edad , Xerostomía/inducido químicamenteRESUMEN
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.
Asunto(s)
Alcaloides/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Elipticinas/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Adulto , Anciano , Anticuerpos/análisis , Antineoplásicos/efectos adversos , Antineoplásicos/inmunología , Carcinoma de Células Renales/secundario , Evaluación de Medicamentos , Elipticinas/efectos adversos , Elipticinas/inmunología , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Hemolytic anemia is an uncommon, but important, complication following the administration of antineoplastic agents. Three types of hemolytic anemia have been reported: microangiopathic hemolytic anemia, immune hemolytic anemia, and oxidative hemolysis. Physicians should be alert to the possibility of this adverse effect in any patient who has a sudden or unexplained drop in hemoglobin concentration while undergoing cancer chemotherapy. If the hemolytic anemia is not recognized and allowed to continue, the consequences may prove to be fatal.
Asunto(s)
Anemia Hemolítica/inducido químicamente , Antineoplásicos/efectos adversos , Anemia Hemolítica/inmunología , Cisplatino/efectos adversos , Coformicina/efectos adversos , Coformicina/análogos & derivados , Doxorrubicina/efectos adversos , Elipticinas/efectos adversos , Humanos , Enfermedades del Complejo Inmune/inducido químicamente , Riñón/irrigación sanguínea , Enfermedades Renales/inducido químicamente , Melfalán/efectos adversos , Metotrexato/efectos adversos , Mitomicinas/efectos adversos , Neoplasias/sangre , Neoplasias/complicaciones , Oxidación-Reducción , Pentostatina , Pirazoles/efectos adversos , Tenipósido/efectos adversosRESUMEN
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.
Asunto(s)
Alcaloides/inmunología , Anemia Hemolítica/inducido químicamente , Anticuerpos/análisis , Elipticinas/inmunología , Anemia Hemolítica/inmunología , Neoplasias de la Mama/tratamiento farmacológico , Elipticinas/efectos adversos , Femenino , Humanos , Estudios Prospectivos , Estudios Retrospectivos , RiesgoRESUMEN
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.
Asunto(s)
Alcaloides/uso terapéutico , Antineoplásicos/uso terapéutico , Elipticinas/uso terapéutico , Neoplasias/tratamiento farmacológico , Adolescente , Adulto , Anciano , Relación Dosis-Respuesta a Droga , Evaluación de Medicamentos , Elipticinas/efectos adversos , Femenino , Hemólisis/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Uremia/inducido químicamenteRESUMEN
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.
Asunto(s)
Alcaloides/uso terapéutico , Antineoplásicos/uso terapéutico , Elipticinas/uso terapéutico , Linfoma/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos/efectos adversos , Evaluación de Medicamentos , Elipticinas/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos PilotoRESUMEN
A broad phase II trial of elliptinium was conducted in 105 evaluable patients with advanced solid tumors. The drug was given as a 60-90-min i.v. infusion at a weekly dose of 100 mg/m2. Of 36 breast cancer patients, one achieved complete and six achieved partial response for an overall response rate of 19%. Responses lasted for 12-56 weeks from initiation of therapy. There was also one partial response among 21 patients with squamous cell carcinoma of the lung. No response could be obtained in 17 patients with colon cancer, 13 patients with head and neck cancer and 18 patients with a wide variety of other malignancies. Myelosuppression was minimal. Nausea and vomiting were the most frequent toxic effects. The drug also produced serious xerostomia and acute intravascular hemolysis. Asthenia was common. Other adverse reactions included fever and chills, transient neurologic and cardiovascular manifestations and renal function impairment. Additional work is needed to define optimal modes of drug administration.
Asunto(s)
Alcaloides/uso terapéutico , Antineoplásicos/uso terapéutico , Elipticinas/uso terapéutico , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos/efectos adversos , Enfermedades de la Médula Ósea/inducido químicamente , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias del Colon/tratamiento farmacológico , Evaluación de Medicamentos , Elipticinas/efectos adversos , Femenino , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Persona de Mediana EdadRESUMEN
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.
Asunto(s)
Alcaloides/efectos adversos , Antineoplásicos/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Elipticinas/efectos adversos , Riñón/efectos de los fármacos , Lesión Renal Aguda/inducido químicamente , Anciano , Elipticinas/uso terapéutico , Femenino , Humanos , Túbulos Renales/patología , Persona de Mediana Edad , Estudios Retrospectivos , Enfermedades Urológicas/inducido químicamente , Enfermedades Urológicas/enzimologíaRESUMEN
A group of 135 patients with osseous metastases from breast cancer were treated with hydroxy-9-methyl-2-ellipticinium (100 mg/m2 weekly). Although it was impossible to grade the response precisely, because only indirect criteria are available for assessing the course of bone metastases (radiographs, quantified 99mTc pyrophosphate scintigrams, CEA), it was considered that an objective response was obtained in 44 cases. These responses lasted from 3 to 17 months. The main characteristic of the compound is its lack of marrow toxicity, a valuable property in osseous lesions, where frequent marrow involvement makes it difficult to use conventional drugs. The major and most unpleasant side effect was an inhibition of salivary secretion, which causes other complications such as tongue mycosis, anorexia, and asthenia. Immunologic disorders were less frequent, and four patients developed severe tubular renal insufficiency.