RESUMEN
The systemic toxicity of an immunoconjugate of blocked ricin and the anti-CD19 monoclonal antibody, anti-B4, was studied in cynomolgus monkeys to evaluate its safety for use in humans. Anti-B4-blocked Ricin (Anti-B4-bR) is a highly cytotoxic immunoconjugate which can kill up to 5 logs of antigen positive target cells at concentrations easily achievable in blood. Subacute toxicity studies with Anti-B4-bR were performed in 20 cynomolgus monkeys and 4 rhesus monkeys, which, unlike humans, do not express the CD19 epitope recognized by the anti-B4 antibody on their B-lymphocytes. Anti-B4-bR was administered to cynomolgus monkeys by 5 daily intravenous bolus injections of 10 or 100 micrograms/kg/day, and non-conjugated blocked ricin was administered by 5 daily intravenous bolus injections of 30 micrograms/kg/day. Total doses of the conjugate of 200, 500, 1000 or 1500 micrograms/kg were also delivered to rhesus monkeys by continuous intravenous infusion over seven days. The clinical signs of toxicity, clinical pathology parameters, and gross and microscopic tissue changes associated with Anti-B4-bR were minimal to moderate where present, and primarily hepatic. In monkeys treated with 5 x 10 micrograms/kg of Anti-B4-bR, lesions were noticeable on day 7 after the start of the treatment but were less severe or absent on day 14, suggesting that the toxic effects were reversible. Clearance of the conjugate from the serum after bolus injections of Anti-B4-bR was evaluated by ELISA and demonstrated an initial t 1/2(alpha) of 1.4-2.0 h and a secondary t 1/2(beta) of about 14 h. Serum concentrations of Anti-B4-bR were about 10-20-fold lower at 24 h as compared to 1 h after each of the 5 bolus injections in monkeys. Continuous infusion of Anti-B4-bR in primates achieved plateau levels of the immunotoxin in blood for almost the entire duration of the infusion. The therapeutic utility of the Anti-B4-bR is currently being evaluated in patients with B-cell malignancies.
Asunto(s)
Antígenos CD/inmunología , Antígenos de Diferenciación de Linfocitos B/inmunología , Inmunotoxinas/toxicidad , Ricina/toxicidad , Animales , Anticuerpos Antiidiotipos/sangre , Especificidad de Anticuerpos , Antígenos CD19 , Linfocitos B/citología , Supervivencia Celular , Reacciones Cruzadas , Humanos , Inmunotoxinas/administración & dosificación , Inmunotoxinas/metabolismo , Infusiones Intravenosas , Inyecciones Intravenosas , Macaca fascicularis , Macaca mulatta , Ratones , Linfocitos T/citología , Células Tumorales CultivadasRESUMEN
A radioimmunoassay procedure for the determination of pirenzepine in either plasma or urine was demonstrated to be both sensitive and specific as well as highly reproducible. The assay could detect levels as low as 1.25 ng/ml. The sensitivity was sufficient to allow the analysis of biological samples from both pharmacokinetic and clinical studies. The two metabolites of pirenzepine, LS 75 and LS 822, did not cross-react with the antiserum. The assay was not affected by a change in anticoagulant or by the presence of several over-the-counter or prescription drugs, even at very high levels. Samples could be frozen and stored for at least a year without affecting the analysis. Repeat analysis could be performed on samples that had been refrozen. Several thousand plasma and urine samples, including plasma samples from severely renally impaired patients, have been analyzed for pirenzepine by the RIA with no interferences having been detected.
Asunto(s)
Pirenzepina/análisis , Animales , Anticoagulantes , Reacciones Cruzadas , Estabilidad de Medicamentos , Congelación , Humanos , Preparaciones Farmacéuticas/análisis , Pirenzepina/análogos & derivados , Conejos , RadioinmunoensayoRESUMEN
Hepatitis B vaccine (Heptavax-B vaccine, Merck Sharp and Dohme) was given by injection into the buttock of 109 healthy workers in a community hospital according to the schedule of the U.S.A. Centers for Disease Control. In only 26% of those between 41 and 65 years of age was antibody to hepatitis B surface antigen found after the full course of vaccination whereas 74% of those aged 18-40 years had detectable antibody. We did not find any significant difference between the responses of males and females in either age group. The unusually poor response may be related to injections being given into the buttock rather than the deltoid region of the arm. We, therefore, recommend that injections of hepatitis B vaccine should be given into the deltoid muscle and that vaccinees should be tested after vaccination for evidence of immunity.
Asunto(s)
Anticuerpos contra la Hepatitis B/biosíntesis , Personal de Hospital , Vacunas contra Hepatitis Viral/inmunología , Adolescente , Adulto , Factores de Edad , Anciano , Femenino , Vacunas contra Hepatitis B , Humanos , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Vacunas contra Hepatitis Viral/administración & dosificaciónRESUMEN
1-Amino-2,4-dibromoanthraquinone (ADBAQ), an intermediate in the production of commercial dyes for wool, silk, and synthetic fibers, was selected for toxicology and carcinogenesis studies in two rodent species. In advance of the 2-year studies, 13-week studies were conducted in male and female F344/N rats and B6C3F1 mice which were fed a diet containing ADBAQ at concentrations of 0, 0.25, 0.50, 1.00, 2.50, and 5.00%. ADBAQ stained the skin and fur red at all doses in rats and at 1.00% and higher concentrations in mice. Lethargy and emaciation were noted at the 2.50% and higher doses in rats of both sexes. In general, the absolute weight of the liver and the liver/organ weight ratios increased in both sexes and species at all doses. Treated rats developed a chronic toxic hepatitis characterized by hepatocytomegaly, centrilobular vacuolar degeneration and necrosis, regenerative nodules, acute necrotizing cholangitis, bile duct hyperplasia, chronic active inflammation in periportal areas, and focal pigmentation. The hepatopathy occurred at all doses in males and at 0.50% and higher in females and correlated with elevations of serum glutamic-pyruvic and glutamic-oxaloacetic transaminases, leukocytosis, and neutrophilia. Hyaline droplet degeneration in the proximal convoluted tubules of the kidneys occurred in male rats, and uterine atrophy was observed in female rats at 1.00% and higher. Anemia occurred in both sexes of rats at all doses and thymic atrophy was observed in both sexes of high-dose rats. In male mice minimal dose-related lesions in the liver included centrilobular glycogen depletion at 1.00% and higher and pigmentation at all doses. At comparable doses, ADBAQ was considered to be markedly toxic in rats and of minimal nonlife-threatening toxicity in mice.
Asunto(s)
Antraquinonas/toxicidad , Carcinógenos/toxicidad , Hígado/efectos de los fármacos , Administración Oral , Animales , Recuento de Células Sanguíneas/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Electrólitos/sangre , Femenino , Hemodinámica/efectos de los fármacos , Riñón/efectos de los fármacos , Hígado/patología , Masculino , Ratones , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Endogámicas F344 , Factores Sexuales , Especificidad de la EspecieRESUMEN
The immunological enhancing activity of staphage lysate on the primary immune response of mice as reflected by specific heteroantibody production to a single antigenic stimulus and on immunoglobulin synthesis was determined. Staphage lysate was administered at different periods in relation to time of sheep erythrocyte injection so that both the inductive and the productive phase of the immune response could be evaluated. Treatment with staphage lysate induced pronounced enhancement of the hemagglutinin response by day 14 regardless of the dose or the time of its administration. Significantly higher antibody levels in the test groups were observed when compared with the control animals, peak antibody titers being 21 days following antigenic challenge. Furthermore, staphage lysate administered without an accompanying antigen evoked a heightened serum immunoglobulin level in mice for a period of more than 14 days after injection. IgG1, IgG2a and IgG2b were significantly elevated as a direct result of this treatment. This increased output of immunoglobulin synthesis and heightened hemagglutinin titers demonstrate that staphage lysate is not only an immunomodulator of cell-mediated immunity, as previously reported, but also an effective immunoadjuvant of the humoral antibody response capability in the host.
Asunto(s)
Adyuvantes Inmunológicos , Formación de Anticuerpos , Bacteriocinas/farmacología , Animales , Eritrocitos/inmunología , Femenino , Hemaglutininas/análisis , Inmunoglobulina G/biosíntesis , Inmunoglobulina M/biosíntesis , Ratones , Ovinos , Factores de TiempoRESUMEN
A pharmacodynamic approach was employed to examine the diuretic effect of chlorthalidone in beagle dogs and to identify parameters necessary for optimization of an oral dosage formulation of this drug. The extensive partitioning of chlorthalidone into erythrocytes was shown to be noninstantaneous, with an in vitro partitioning half-life of 18 min. In vivo studies using oral and intravenous solutions confirmed this finding. Additionally, the diuretic effect was demonstrated to be related to the drug concentration in the plasma fraction. These studies led to the development of a relevant pharmacokinetic model which highlighted the importance of the oral absorption rate on the diuretic efficacy of chlorthalidone. A novel, rapidly dissolving, stabilized, amorphous chlorthalidone tablet formulation was compared to various oral solution and tablet formulations. Pharmacokinetic analysis by classical compartmental models and by moment techniques demonstrated that the rapidly dissolving tablet formulation was bioequivalent to an oral solution of chlorthalidone. Preparations containing crystalline chlorthalidone are shown to be incompletely absorbed, and the rates of absorption favor partitioning into the erythrocyte fraction. It is projected from the pharmacodynamic model that the novel chlorthalidone preparation optimizes plasma levels necessary to invoke a diuretic response.
Asunto(s)
Clortalidona/farmacología , Química Farmacéutica , Clortalidona/sangre , Clortalidona/metabolismo , Diuresis/efectos de los fármacos , Estabilidad de Medicamentos , Eritrocitos/metabolismo , Humanos , Inyecciones Intravenosas , Riñón/metabolismo , Cinética , Modelos Biológicos , Solubilidad , Soluciones , ComprimidosRESUMEN
The genotoxic potential of acephate technical (AT) in vitro and in vivo has been studied in bioassays detecting primary DNA damage, chromosomal alterations, and gene mutation. Results from in vitro assays have ranged from negative to weakly positive; AT is apparently a direct-acting agent in these tests. However, expressed in terms of molar potency, AT has generally been at least 100-1000 times less potent than known positive mutagens tested in vitro. Following in vivo exposure at maximum tolerated doses, AT did not induce chromosomal aberrations, sister chromatid exchange, or micronuclei in mouse bone marrow cells; a dominant lethal study in mice was also negative. In a supplemental study, no induced chromosomal aberrations or sister chromatid exchange could be detected in lymphocytes from a pair of cynomolgus monkeys following exposure to AT at a low dose level for 20 days. At dose levels limited by toxicity, no positive results were observed for induction of sex-linked, recessive lethality in D. melanogaster. Acephate technical (ORTHENE) appears to present little or no genetic hazard to in vivo mammalian systems.
Asunto(s)
Médula Ósea/efectos de los fármacos , Mutágenos/toxicidad , Compuestos Organotiofosforados/toxicidad , Administración Oral , Animales , Aberraciones Cromosómicas , Femenino , Feto/efectos de los fármacos , Macaca fascicularis , Masculino , Ratones , Mitosis/efectos de los fármacos , Pruebas de Mutagenicidad , Fosforamidas , Embarazo , Salmonella typhimurium/efectos de los fármacos , Intercambio de Cromátides Hermanas/efectos de los fármacosRESUMEN
Diagnosis of cancer via measurement of carcinoembryonic antigen (CEA) levels has been unreliable in early neoplastic stages. In order to improve diagnostic reliability, other cytological parameters were examined with CEA. Fifty specimens of effusion fluid were obtained from 40 hospitalized patients and the levels of CEA determined by radioimmunoassay in conjunction with application of an immunoperoxidase procedure. Simultaneous morphologic assessment was performed without knowledge of the immunoassay findings. In 8 documented cases of mammary cancer, all effusion fluid specimens had CEA levels of 16-1074 ng/ml, 7 cases had morphologically positive cells, but only 3 had a peroxidase positive reaction. Except for one case of ovarian papillary adenocarcinoma, the remaining patients were cancer free, had CEA levels of less than 15 ng/ml and only 2 cases (including the ovarian tumor patient) gave positive peroxidase responses. The presence of mammary metastatic duct carcinoma correlated 88% with CEA measurements but peroxidase response was not diagnostically helpful.
Asunto(s)
Neoplasias de la Mama/diagnóstico , Antígeno Carcinoembrionario/análisis , Líquidos Corporales/citología , Líquidos Corporales/inmunología , Carbazoles , Femenino , Histocitoquímica , Humanos , Técnicas para Inmunoenzimas , Derrame Pleural/inmunología , Derrame Pleural/patología , RadioinmunoensayoRESUMEN
A reliable, sensitive, and specific radioimmunoassay (RIA) procedure for the quantitation of clonidine in plasma and other biological fluids was developed. The detection limit of the assay is 2 pg based on a 200 microliters sample. Nine commonly used drugs were found not to interfere with the RIA. The utility of the assay was demonstrated in a bioavailability study of clonidine conducted with 24 healthy subjects. Clonidine was readily quantitated in plasma over 4 half-lives. This assay is suitable for pharmacokinetic and bioavailability studies as well as therapeutic drug monitoring of patients.
Asunto(s)
Clonidina/análisis , Adolescente , Adulto , Clonidina/sangre , Clonidina/orina , Humanos , Masculino , Radioinmunoensayo/métodosRESUMEN
A high-performance liquid chromatographic assay usable for clinical monitoring of chlorthalidone in biological fluids was developed. Extraction efficiency was greater than 80% for blood and urine using a rapid, disposable column cleanup procedure. Chlorthalidone could be reliably measured in the range of 100-4,000 ng/ml in biological fluids with excellent day-to-day reproducibility and within-day precision. Chlorthalidone was found to be stable at -20 degrees C in blood and urine for at least 1 year, permitting repeat assays and large clinical studies to be conducted. The pharmacokinetics of chlorthalidone was studied in 24 subjects over a 120-h time interval following a single dose. chlorthalidone has a long terminal half-life in whole blood of 49 h, with peak concentrations occurring 8-10 h after oral dosing. During the first 12 h after dosing, chlorthalidone was rapidly excreted into urine followed by a slower phase with a half-life of 49 h.
Asunto(s)
Clortalidona/sangre , Cromatografía Líquida de Alta Presión/métodos , Adolescente , Adulto , Clortalidona/orina , Congelación , Humanos , Cinética , Masculino , Preservación Biológica , Factores de TiempoRESUMEN
Infection with Mycobacterium intracellulare serotype 10 was diagnosed in 2 rhesus monkeys (Macaca mulatta) in a closed colony of 90 animals. The clinicopathologic presentation in 1 animal with advanced disease was characterized by a precipitous weight loss, therapeutically unresponsive diarrhea, anemia, weakness, prostration, refractory tuberculin tests (using mammalian old tuberculin and M bovis purified protein derivative tuberculin), and disseminated granulomas in the lungs, spleen, liver, kidneys, lymph nodes, salivary glands, and intestines. The lamina propria throughout the large and small intestines was infiltrated with mycobacteria-laden macrophages. Severe hypoproteinemia, hypoalbuminemia, hypoglobulinemia, mild hypocalcemia, and edema were compatible with a malabsorption-like syndrome. The 2nd animal was clinically normal, but a weak positive tuberculin reaction to M bovis purified protein derivative at 72 hours necessitated euthanasia. This animal's disease was characterized by microgranulomas in the lungs, bronchial lymph nodes, liver, and pancreas, without involvement of the gastrointestinal tract. There was no evidence of M intracellulare infection in the remaining 88 animals in the colony, as determined by mycobacterial cultures of tracheobronchial washings, additional tuberculin testing, thoracic radiography, and mycobacterial culture of the drinking water. Tuberculin testing and thoracic radiographs of personnel working with the nonhuman primates were also negative. These cases were considered to be important because both animals were infected with the same serotype and because there has been an increasing number of isolations of this organism in human infections throughout Massachusetts. Drug-sensitivity testing revealed the organism to be sensitive to cycloserine and resistant to isoniazid, rifampin, ethambutol, streptomycin, kanamycin, and pyrazinamide.
Asunto(s)
Enfermedades de los Monos/diagnóstico , Infecciones por Mycobacterium/veterinaria , Animales , Femenino , Macaca mulatta , Infecciones por Mycobacterium/diagnósticoRESUMEN
Feasibility of utilizing human tumors as first transplant generation xenografts in the normal immunocompetent mouse for determining tumor sensitivity to chemotherapeutic agents was demonstrated by applying subrenal capsule (SRC) assay methodology to fresh surgical explants in a six-day time frame. A total of 37 human breast tumors were tested in assays in which 254 xenografts were implanted into control animals. Fifty (20%) of the controls showed some degree of partial regression in the six-day assay period. Using a mean control growth having a positive change in tumor size as the criterion for evaluability, first transplant generation human breast tumors provided an evaluable assay rate of 86%. A tumor response profile was obtained as a result of testing seven clinically active drugs against 32 previously untreated breast cancers. The pattern of responses obtained indicated that no single agent was active against all tumors, nor were tumors which were responsive to one agent necessarily responsive to another, suggesting the feasibility of predicting individual tumor response to specific chemotherapeutic agents. Had these seven drugs been developmental agents of unknown activity which were being tested for the first time against such a panel of human tumors the result would have not only predicted their clinical activity, but the tumor response rates would have also provided an indication of the relative potential of each drug for the specific treatment of breast cancer.
Asunto(s)
Antineoplásicos/uso terapéutico , Evaluación Preclínica de Medicamentos/métodos , Adenocarcinoma/tratamiento farmacológico , Animales , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma Intraductal no Infiltrante/tratamiento farmacológico , Neoplasias del Colon/tratamiento farmacológico , Femenino , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Desnudos , Persona de Mediana Edad , Trasplante de Neoplasias , Neoplasias Experimentales/tratamiento farmacológico , Trasplante HeterólogoRESUMEN
The immunopotentiating activity of staphage lysate (SPL) was evaluated in terms of its immune protection against lethal bacterial infection and its antitumor activity. Mice were pretreated weekly with 10(8) viable, Staphylococcus aureus, strain 18Z for 3 weeks (Induction), followed by intraperitoneal SPL injections (Elicitation) at various times in relation to infectious challenge or tumor implantation. Induction without elicitation, or elicitation alone failed to provide protection against Klebsiella pneumoniae infection and resulted in only 30-40% survival against homologous infection with pathogenic S. aureus type III, whereas combined induction and elicitation produced enhanced resistance induction and elicitation regimens resulted in 50% and 80-100% survival in mice inoculated with K. pneumoniae and S. aureus, respectively. SPL had no antitumor effect in mice implanted with median survival time resulting from induction and elicitation in animals implanted which Ehrlich's ascites. This enhancement of immune resistance may possibly be related to activation of thymus-modulated lymphocytes and macrophages by SPL.
Asunto(s)
Adyuvantes Inmunológicos , Bacteriocinas/farmacología , Animales , Carcinoma de Ehrlich/inmunología , Femenino , Inmunidad/efectos de los fármacos , Infecciones por Klebsiella/inmunología , Klebsiella pneumoniae , Ratones , Sarcoma 180/inmunología , Infecciones Estafilocócicas/inmunología , Zimosan/farmacologíaRESUMEN
Hormone release rates from biodegradable cylindrical implants consisting of a physical matrix of [14C]levonorgestrel and copolymers of [3H]lactic and glycolic acids have been monitored in rats. Two copolymers were evaluated: one consisted of 90 parts L-lactide/10 parts glycolide (90L/10G) containing 33 or 50% hormone by weight, and the other of 50 parts DL-lactide/50 parts L-lactide (50DL/50L) containing 50% hormone. For each system, 4-6 rods (0.8 x 16 mm) providing 19 mg of steroid per rat were subcutaneously implanted into the scapular regions of 5 rats, and 14C and 3H in faeces and urine were determined weekly for 90-724 days. An initial burst of hormone release, peaking at approximately 90 microgram day-1, occurred in the first two weeks. This was followed by an approximately 10-30 microgram day-1 for the 90L/10G system containing 33% hormone, a more uniform rate of approximately 25 microgram day-1 for the 50DL/50L system and the highest rate of approximately 40 microgram day-1 for the 90L/10G system containing 50% hormone. 3H and 14C in residual implants of 90L/10G with 33% hormone removed from animals dying of natural causes during the test were assayed. For this system 3H activity decreased by over 50% within 250 days, compared with < 25% loss in 14C activity. The amounts of 3H and 14C released were similar over much of the subsequent test period. At the end of the test both polymer and drug were essentially depleted. All animals with the 50DL/50L system died late in the test period. Between days 609 and 724 from 13.7-27.2% initial 14C and from 10.0-22.1% initial 3H was measured in recovered rods. Microscopic inspection of recovered rods showed a loss of core material and tissue encapsulation. There were no signs of local tissue irritation or systemic toxicity.
Asunto(s)
Norgestrel/administración & dosificación , Animales , Biodegradación Ambiental , Implantes de Medicamentos , Heces/análisis , Femenino , Glicolatos , Lactatos , Levonorgestrel , Norgestrel/metabolismo , Polímeros , Ratas , Factores de TiempoRESUMEN
Previous findings at various laboratories indicated that cannabinoids distribute to sexual behavior centers in the brain, and endocrine aberrations have consistently been observed in animals treated with cannabis constituents. Subacute and chronic studies were performed to monitor hormone changes in rats and monkeys exposed to marihuana smoke or pure cannabinoids. In oral studies, young Fischer rats of both sexes were given delta 9-tetrahydrocannabinol (delta 9-THC) doses of 2, 10, or 50 mg/kg for 14--180 d and pregnant rats received 1, 5 or 10 mg/kg during gestation and lactation. Other male rats were exposed to marihuana smoke at delta 9-THC doses of 2 or 4 mg/kg for 14 d. Rhesus monkeys of either sex were given oral cannabidiol doses of 30, 100, and 300 mg/kg for 90 d. Serum pituitary, steroid, and thyroid hormone levels were determined by radioimmunoassay. Marihuana smoke (and oral delta 9-THC) depressed testosterone 20--30% and triiodothyronine 17--29%. In pregnant rats, small doses of delta 9-THC suppressed luteinizing hormone, but larger doses elevated both follicle-stimulating hormone and estrogens (approximately 50--100%) without affecting progesterone levels. Prolonged oral administration of delta 9-THC to young rats tended to increase gonadotropins, to which tolerance developed in males. Cannabidiol-treated monkeys responded with slight elevations in luteinizing hormone and follicle-stimulating hormone in males, whereas steroid hormones were essentially unchanged for both sexes. Hormone imbalance may explain cannabinoid-induced embryotoxicity and impaired gonadal function.
Asunto(s)
Cannabinoides/farmacología , Glándulas Endocrinas/efectos de los fármacos , Hormonas/sangre , Administración Oral , Aerosoles , Animales , Cannabidiol/farmacología , Cannabinoides/administración & dosificación , Cannabis , Dronabinol/farmacología , Femenino , Haplorrinos , Lactancia/efectos de los fármacos , Macaca mulatta , Masculino , Embarazo , Ratas , Ratas Endogámicas F344RESUMEN
Immunosuppression evoked by delta 9-tetrahydrocannabinol (delta 9-THC) has been a consistent finding in rats but the development of tolerance to this phenomenon has not been explored. Therefore, Fischer rats of both sexes were orally given delta 9-THC at 6 or 12 mg/kg or sesame oil as vehicle control for 5-26 days before and after I.P. antigenic stimulation with sheep red blood cells (SRBC). delta 9-THC doses were relevant to those of man and produced mild CNS-inhibition followed by CNS-stimulation, tolerance developing to both behavioral phases. The primary immune response was evaluated by determining splenic antibody-forming cells (AFC), hemagglutinin (HT) and/or hemolysin (HS) titers. Simultaneous administration of delta 9-THC and SE induced dose-related splenic atrophy and reduced AFC proliferation as well as HT and HS responses. These changes were not elicited by sesame oil. Tolerance did not develop to immunosuppression during 26 days of cannabinoid treatment. delta 9-THC given 3 days post SRBC inoculation induced immunosuppression at 12 but not 6 mg/kg. Immunosuppression was directly related to delta 9-THC rather than to non-specific debilitating factors since body weights are stable. The inductive phase of the primary immune response was most sensitive to impairment although the reproductive phase was also affected at the high dose level.
Asunto(s)
Dronabinol/farmacología , Inmunosupresores , Animales , Tolerancia a Medicamentos , Femenino , Masculino , Ratas , Ratas Endogámicas F344RESUMEN
The subrenal capsule technique proved effective in demonstrating that the growth of human tumors in normal, immunocompetent animals for 6 days was quantifiable in ocular micrometer units. Positive growth was demonstrable not only with human tumors that had been established in serial transplantation in athymic nude mouse hosts, but also with primary surgical explants. Growth rates of transplantation-established xenograft systems were similar whether implanted in athymic nude or in normal immunocompetent animals indicating that the 6-day time-frame successfully evades growth inhibitory effects of immunologic origin. Immunosuppression with a single dose of cyclophosphamide did not appear to affect growth rate, but permitted the tumors to grow larger extending the time to reach peak size. Significantly, xenografts of primary surgical explants showed positive growth more frequently in 6 days (82%) in the immunocompetent animal than in 11 days (30%) in the immunodeficient athymic nude mouse.
Asunto(s)
Trasplante de Neoplasias , Animales , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Femenino , Humanos , Terapia de Inmunosupresión , Riñón/inmunología , Ratones , Ratones Desnudos/inmunología , Trasplante HeterólogoRESUMEN
Intradermal injections of MER-BCG 0.1 mg or 0.2 mg at each of 10 multiple sites, led to local granuloma formation. The nodules reached approximately 10 mm in diameter, ulcerated and were accompanied by granulomatous changes in the regional lymph nodes. Six or twelve successive treatments (each including 10 injections) at 4 week intervals produced the same histopathological lesions but no changes in hematological and blood chemical parameters or general morphology and no changes in general condition with exception of occasional weight loss in a few animals. Injection with 0.01 or 0.001 mg/site produced similar, though less severe, skin lesions but no changes in the draining lymph nodes. The immunogenicity of MER-BCG was characterized by granuloma formation, a positive skin response to old tuberculin, and a positive lymphocyte transformation to PPD tuberculin, thus indicating stimulation of cell-mediated immune responses. However, there was a decreased responsiveness to PHA and PPD with continuing treatment with MER-BCG. The decreased responsiveness and accumulation of numerous depots of antigen would suggest an "immunologic paralysis" contraindicating the administration of excessive amounts of MER-BCG during immunotherapy. A specific humoral response to the administration of MER-BCG was not detected, but an MER-BCG dose independent decrease in albumin associated with a non-specific, dose related elevation in serum IgG was observed.
Asunto(s)
Adyuvantes Inmunológicos/farmacología , Vacuna BCG/farmacología , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/toxicidad , Animales , Formación de Anticuerpos/efectos de los fármacos , Vacuna BCG/administración & dosificación , Vacuna BCG/toxicidad , Perros , Femenino , Inmunidad Celular/efectos de los fármacos , Inyecciones Intradérmicas , Activación de Linfocitos/efectos de los fármacos , MasculinoRESUMEN
The concept of "induction and elicitation," propounded by Stuart Mudd, circumvents the dangers of infecting the immunologically impaired individual without abrogating the effectiveness of the antigenic stimulus provided by an initial infection with living organisms. Mudd's concept utilizes the ubiquitous and naturally established delayed type hypersensitivity to Staphylococcus aureus as the primary induction step for the more effective use of bacterial fractions, such as staphylococcal phage lysate, a potent immunizing agent, commercially licensed and available, in the subsequent elicitation of a nonspecific, cell-mediated immune response. The results of an exploratory study in which induction and elicitation were applied as an immunotherapeutic modality, in combination with surgery, in a metastasizing animal tumor model (the F344 rat) are presented.
Asunto(s)
Hipersensibilidad Tardía , Inmunoterapia , Neoplasias Mamarias Experimentales/terapia , Staphylococcus aureus/inmunología , Animales , Antígenos Bacterianos/administración & dosificación , Femenino , Ratas , Ratas Endogámicas F344RESUMEN
Based upon the hypothesis that a factor most pertinent to the absence of an effective immune response in cancer is the inadequacy of the antigenic stimulus provided by the neoplasm, either in terms of weak immunogenicity of the tumor antigen or of the necessary antigen mass available to the reticuloendothelial tissues at any one time for effective sensitization, the host immune response capabilities were stimulated within a time frame synchronous with a greater release of tumor antigens. In the treatment of a metastasizing, solid tumor model syngeneic with F344 rats, immunotherapy was most effectively applied in combinations with chemotherapy and/or localized radiotherapy, therapeutic modalities that induced a degree of oncolysis and tumor resorption. Surgery combined with chemotherapy permitted evaluation of therapeutic effects against metastases. The methanol-soluble fraction of Mycobacterium butyricum was used as the nonspecific immunologic adjuvant.