RESUMEN
Calcitriol potentiates the effect of multiple chemotherapy agents in a variety of tumour models. In this study, we examine whether calcitriol increases chemotherapy or tyrosine kinase inhibitor in vitro cytotoxicity in canine mastocytoma C2 cells. We also evaluate the in vivo effect of DN101, a highly concentrated oral formulation of calcitriol designed specifically for cancer therapy, as a single-agent therapy in dogs with mast cell tumours (MCTs). Calcitriol exhibits synergistic, antiproliferative activity when used in combination with CCNU, vinblastine, imatinib or toceranib in vitro. The concentrations required for 50% growth inhibition were generally two- to six-fold lower when the drugs were used in combination than when used individually. High-dose oral calcitriol induced remission in 4 of 10 dogs (one complete remission, three partial remissions), although the majority experienced toxicity, necessitating discontinuation of the trial. Further evaluation of calcitriol in combination therapy for dogs with MCTs is warranted.
Asunto(s)
Calcitriol/uso terapéutico , Agonistas de los Canales de Calcio/uso terapéutico , Enfermedades de los Perros/tratamiento farmacológico , Mastocitoma/veterinaria , Neoplasias Cutáneas/veterinaria , Animales , Antineoplásicos/farmacología , Benzamidas , Western Blotting/veterinaria , Calcitriol/efectos adversos , Calcitriol/farmacología , Agonistas de los Canales de Calcio/efectos adversos , Agonistas de los Canales de Calcio/farmacología , Línea Celular Tumoral , Perros , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Femenino , Mesilato de Imatinib , Indoles/farmacología , Lomustina/farmacología , Masculino , Mastocitoma/tratamiento farmacológico , Mastocitoma/patología , Piperazinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirimidinas/farmacología , Pirroles/farmacología , Receptores de Calcitriol/análisis , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Resultado del Tratamiento , Vinblastina/farmacologíaRESUMEN
This prospective study evaluated the efficacy and safety of hydroxyurea (HU) in dogs with measurable mast cell tumours (MCTs). Dogs were treated with HU at 60 mg kg(-1)per os q24h for 14 days then 30 mg kg(-1) q24h thereafter or until MCT recurrence. Forty-six dogs were enrolled. The overall response rate was 28%. Two dogs had a complete response (CR) for 256 and 448 days, respectively. Eleven dogs had a partial response for a median duration of 46 days (range, 28-189 days). Grade 2 to 4 neutropenia occurred in eight dogs and grade 4 thrombocytopenia in two. Grade 3-4 anaemia occurred in seven dogs; overall, there was a significant decrease in haematocrit after treatment with HU. The median drop in haematocrit was 10%. This study demonstrated that HU has activity in the treatment of MCTs with mild anaemia being the primary adverse event.
Asunto(s)
Antineoplásicos/uso terapéutico , Enfermedades de los Perros/tratamiento farmacológico , Hidroxiurea/uso terapéutico , Mastocitoma Cutáneo/veterinaria , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Perros , Esquema de Medicación/veterinaria , Femenino , Hidroxiurea/administración & dosificación , Hidroxiurea/efectos adversos , Recuento de Leucocitos/veterinaria , Masculino , Mastocitoma Cutáneo/tratamiento farmacológico , Estudios Prospectivos , Trombocitopenia/inducido químicamente , Trombocitopenia/veterinaria , Resultado del TratamientoRESUMEN
In mice and people, administering corticosteroids before chemotherapy can reduce the severity of myelosuppression without reducing antitumour effects. This study investigated whether pretreatment with dexamethasone would reduce the incidence of grade 4 neutropenia in dogs receiving CCNU. Twenty-five dogs received dexamethasone [0.1 mg kg(-1) per os (PO) every 12 h] for 5 days and on the sixth day received CCNU (90 mg m(-2) PO). Historical dogs (n = 67) received CCNU alone (90 mg m(-2) PO). Forty-five percent of historical dogs had grade 4 neutropenia, while 64% of dogs pretreated with dexamethasone had grade 4 neutropenia (P = 0.16). Dexamethasone plasma levels were quantified by enzyme-linked immunosorbent assay in three healthy dogs. Peak plasma concentrations after a single oral 0.1-mg kg(-1) dose were <80 ng mL(-1), the minimum level associated with chemoprotective effects of dexamethasone in people. Pretreatment with dexamethasone did not reduce the incidence of grade 4 neutropenia in dogs receiving CCNU.
Asunto(s)
Médula Ósea/efectos de los fármacos , Dexametasona/farmacología , Enfermedades de los Perros/sangre , Enfermedades de los Perros/tratamiento farmacológico , Glucocorticoides/farmacología , Neutropenia/veterinaria , Animales , Antineoplásicos Alquilantes/administración & dosificación , Perros , Relación Dosis-Respuesta a Droga , Ensayo de Inmunoadsorción Enzimática , Lomustina/administración & dosificación , Neutropenia/sangre , Neutropenia/tratamiento farmacológico , New York , Facultades de Medicina Veterinaria , Resultado del TratamientoRESUMEN
BACKGROUND: Pleotropic-glycoprotein (P-gp)-mediated resistance is the usual cause of relapse in dogs with lymphoma. 1-(2-chloroethyl)3-cyclohexyl-1-nitrosurea (CCNU) and 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide (DTIC) are alkylating agents that are not affected by P-gp and lack cross-resistance to each other. A combination protocol offers the advantage of improved summation dose and synergistic activity. HYPOTHESIS: A combination of CCNU and DTIC that is well tolerated can be used to treat dogs with lymphoma that developed resistance or failed to respond to previously administered chemotherapy. ANIMALS: Fifty-seven dogs with lymphoma that were resistant to treatment with standard chemotherapy (L-CHOP; L-asparaginase, cyclophosphamide, doxorubicin, vincristine, prednisone). METHODS: Prospective phase I and II trials were performed. CCNU was given PO immediately before a 5-h IV infusion of DTIC. Concurrent antiemetics and prophylactic antibiotics were used. Treatments were administered every 4 weeks. RESULTS: Based on the results of 8 dogs in the phase I study, CCNU at 40 mg/m(2) PO combined with DTIC at 600 mg/m(2) IV was used to treat 57 dogs with resistant lymphoma. Thirteen (23%) dogs had a complete response (CR) for a median of 83 days and 7 (12%) had a partial response for a median of 25 days. The median L-CHOP CR duration of the dogs that did not respond to CCNU-DTIC was significantly longer than that of the dogs that did achieve remission with CCNU-DTIC (225 days versus 92 days, P= .02). The principal toxic event was neutropenia; the median neutrophil count 7 days after treatment was 1,275 cells/microL. Increases in alanine transaminase activity, possibly associated with hepatotoxicity, were detected in 7 dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: A combination of CCNU and DTIC can be an effective option to rescue dogs with resistant lymphoma.
Asunto(s)
Antineoplásicos/uso terapéutico , Dacarbazina/uso terapéutico , Enfermedades de los Perros/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Lomustina/uso terapéutico , Linfoma/veterinaria , Animales , Antineoplásicos/efectos adversos , Dacarbazina/efectos adversos , Perros , Relación Dosis-Respuesta a Droga , Femenino , Lomustina/efectos adversos , Linfoma/tratamiento farmacológico , MasculinoRESUMEN
OBJECTIVE: To evaluate response rate and duration of malignant melanomas in dogs treated with carboplatin. DESIGN: Retrospective study. ANIMALS: 27 client-owned dogs with spontaneously occurring measurable malignant melanomas. PROCEDURE: Records of dogs with melanomas treated with carboplatin from October 1989 to June 2000 were reviewed. Carboplatin was administered IV at doses of 300 or 350 mg/m2 of body surface area. Response to treatment and evidence of drug toxicity were determined. RESULT: Response to treatment could be evaluated in 25 dogs. Of those, overall response rate was 28%. One dog had a complete response, 6 (24%) dogs had a partial response (> 50% reduction in tumor burden). Median duration of partial response was 165 days. Eighteen dogs had stable disease (n = 9; 36%) or progressive disease (9; 36%). Response to treatment was significantly associated with carboplatin dose on a milligram per kilogram basis (15.1 mg/kg 16.9 mg/lb] of body weight vs 12.6 mg/kg [5.7 mg/lb]). Evidence of gastrointestinal toxicosis could be assessed in 27 dogs. Mean body weight of 5 dogs that developed gastrointestinal toxicosis was significantly less than that of 22 dogs without gastrointestinal toxicosis (9.9 kg [21.8 lb] vs 19.3 kg [42.5 lb]). CONCLUSIONS AND CLINICAL RELEVANCE: Carboplatin had activity against macroscopic spontaneously occurring malignant melanomas in dogs and should be considered as an adjunctive treatment for microscopic local or metastatic tumors. Gastrointestinal toxicosis was associated with body weight. Because small dogs are more likely to have adverse gastrointestinal effects, gastrointestinal protectants should be considered for these patients.
Asunto(s)
Antineoplásicos/uso terapéutico , Carboplatino/uso terapéutico , Enfermedades de los Perros/tratamiento farmacológico , Melanoma/veterinaria , Neoplasias Cutáneas/veterinaria , Animales , Antineoplásicos/efectos adversos , Peso Corporal , Carboplatino/efectos adversos , Enfermedades de los Perros/patología , Perros , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Melanoma/tratamiento farmacológico , Melanoma/secundario , Estudios Retrospectivos , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Resultado del TratamientoRESUMEN
Surgery, chemotherapy, and irradiation have been used singly or in combination to treat dogs with cutaneous grade-2 mast cell tumors (MCT). However, optimal treatment has not been established. At The Animal Medical Center, 32 dogs with grade 2, stage 0 MCT received cobalt radiation treatment to a dose of 54 Gy; 94% had a disease-free interval of 1 year. The 2-,3-,4-, and 5-year disease-free intervals were 86%. Survival rates were 100% for 1 year and 96% for 2 to 5 years, with only 1 death caused by MCT. Primary site was not a prognostic factor for survival in this study. Minimal toxicity was observed and was limited to acute cutaneous reactions. Late-term reactions to radiation therapy were mild and considered acceptable in all cases. No deaths occurred due to treatment, and no dog was eliminated from the study because of radiation therapy toxicity. Radiation therapy appears to be an effective treatment for dogs with grade 2, stage 0 MCT.
Asunto(s)
Enfermedades de los Perros/radioterapia , Sarcoma de Mastocitos/veterinaria , Radioterapia/veterinaria , Neoplasias Cutáneas/veterinaria , Animales , Enfermedades de los Perros/mortalidad , Enfermedades de los Perros/patología , Perros , Femenino , Masculino , Sarcoma de Mastocitos/patología , Sarcoma de Mastocitos/radioterapia , Pronóstico , Estudios Prospectivos , Radioterapia/mortalidad , Radioterapia/normas , Dosificación Radioterapéutica , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/radioterapia , Tasa de SupervivenciaRESUMEN
Incubation of isolated Chinese hamster ovary cell nuclei, equilibrated in an atmosphere containing 2% O2, with glutathione, cysteine, or cysteamine resulted in a decrease in the number of X-ray-induced DNA double-strand breaks (DSBs), determined by pH 9.0 filter elution. In the absence of exogenous thiol, no sensitization was observed with the addition of N-ethylmaleimide, indicating that endogenous thiols were not present at significant levels. Protection by 0.3 mM glutathione was not enhanced by the addition of exogenous glutathione S-transferases or by glutathione peroxidase. The data were analyzed according to a simple competition model with various hypotheses. Cysteamine was more than an order of magnitude more effective than the other thiols tested, on a molar basis, in preventing DSB formation. Depending on the hypothesis used to evaluate the data, glutathione was either much less effective, on a molar basis, in preventing the bulk of the DSBs or was capable of preventing only approximately 55% of the damage, regardless of concentration. These data suggest that natural thiols other than glutathione may contribute to cellular radioprotection even if their concentration is much lower than that of glutathione. The data also suggest that despite the relative inefficiency of glutathione as a radioprotector, some areas of oxygenated tissues--where the oxygen tension falls below 2%--may be protected by glutathione concentrations in the physiological range of 3-20 mM.
Asunto(s)
Cisteamina/farmacología , Cisteína/farmacología , Daño del ADN , ADN/efectos de los fármacos , ADN/efectos de la radiación , Glutatión/farmacología , Oxígeno/fisiología , Protectores contra Radiación/farmacología , Animales , Células CHO , Núcleo Celular/efectos de los fármacos , Núcleo Celular/efectos de la radiación , CricetinaeRESUMEN
We have found that kidney glutathione and cysteine content in C3H mice can be increased by intraperitoneal administration of either glutathione (GSH) or glutathione disulfide (GSSG). Kidney thiol content is maximal 20-60 min after administration of 1000 mg/kg glutathione and returns to normal values by 2 h. The same time-course of thiol perturbation was observed when acivicin, an inhibitor of gamma-glutamyl transpeptidase, was administered 15 min prior to GSSG administration. The increase in kidney thiols after GSSG administration appears to saturate, with little additional increase as the administered dose is increased above 750 mg/kg. There was no significant change in liver GSH or cysteine after GSSG administration. We suggest that glutathione administration may provide a strategy for selective radioprotection or chemoprotection of specialized cells which can effectively utilize systemic GSH precursors.