RESUMEN
CT-2584, an anticancer agent that inhibits phospholipid signaling, is under development by Cell Therapeutics Inc (CTI) as a potential treatment for various types of cancer. Phase II trials are underway for the treatment of prostate cancer and soft-tissue sarcoma [306617], [324290]. According to CIBC World Markets, completion of enrolment for these trials was expected in the fourth quarter of 2000. Furthermore, the initiation of phase II/III trials in combination with taxotere for the treatment of prostate cancer was anticipated in the second half of 2000, as were phase I/II trials in combination with cisplatin for the treatment of other cancers, including lung cancer [396582]. Results of a phase II study in patients with soft-tissue sarcomas evaluating pharmacokinetics, tolerance and therapeutic activity were presented at the 2000 American Society of Clinical Oncology (ASCO) meeting [367283]. Further data are expected to be presented at the ASCO meeting in May 2001 [396582]. Cell Therapeutics is seeking development and commercialization partners for CT-2584 [386398].
Asunto(s)
Antineoplásicos/farmacología , Drogas en Investigación , Xantinas/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/farmacología , Fatiga/inducido químicamente , Hematuria/inducido químicamente , Humanos , Masculino , Estructura Molecular , Ácidos Fosfatidicos/metabolismo , Fosfatidilcolinas/metabolismo , Fosfolipasa D/antagonistas & inhibidores , Neoplasias de la Próstata/tratamiento farmacológico , Sarcoma/tratamiento farmacológico , Células Tumorales Cultivadas , Xantinas/química , Xantinas/farmacocinética , Xantinas/uso terapéuticoRESUMEN
OBJECTIVE: To investigate Ki-67 and p21Waf1/Cip1 expression and apoptosis, before and after treatment, in tumour biopsies obtained from patients with superficial bladder cancer who underwent vinorelbine intravesical therapy. PATIENTS AND METHODS: Twenty patients with high-risk superficial bladder cancer (including one or more of the following parameters: tumour diameter > 3 cm, histological grade 3, or multicentric tumours) were treated 1-6 times (weekly) with intravesical vinorelbine (50 mg/mL) instillations. Transurethral tumour marker biopsies were obtained one week before the first instillation of the drug and one week after the last. The biopsies were immunostained for Ki-67 and p21Waf1/Cip1 with monoclonal antibodies, on tissue sections derived from paraffin-embedded samples obtained before and after vinorelbine treatments. In addition, apoptosis was determined using a terminal deoxynucleotidyl transferase-mediated dUTP biotin nick-end labelling (TUNEL) technique. RESULTS: There were no significant differences in the cell proliferation marker Ki-67 in biopsies taken before or after treatment. However, p21Waf1/Cip1 showed significantly higher expression in biopsies obtained after vinorelbine treatment, with median (range) values of 40 (20-90)% before and 70 (50-80)% after (P < 0.001, paired nonparametric Wilcoxon test). The apoptotic index was significantly higher after vinorelbine therapy, with median (range) values of 0.89 (0.06-3.8)% before and 2.25 (0.17-18.7)% after treatment (P < 0.001, paired nonparametric Wilcoxon test). Despite the brief treatment and few patients there was a clinical response in nine patients, together with low toxicity in all. CONCLUSION: The intravesical treatment of tumours with vinorelbine affects p21Waf1/Cip1 expression without blocking cell proliferation, although increasing apoptosis. The preliminary results suggest that vinorelbine may be useful for treating superficial bladder tumours, and thus a phase II study is warranted.
Asunto(s)
Antineoplásicos Fitogénicos/administración & dosificación , Carcinoma de Células Transicionales/tratamiento farmacológico , Ciclinas/metabolismo , Antígeno Ki-67/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Vinblastina/administración & dosificación , Administración Intravesical , Anciano , Anciano de 80 o más Años , Apoptosis/efectos de los fármacos , Biopsia/métodos , Carcinoma de Células Transicionales/metabolismo , Carcinoma de Células Transicionales/patología , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Femenino , Humanos , Inmunohistoquímica/métodos , Etiquetado Corte-Fin in Situ , Masculino , Persona de Mediana Edad , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/patología , Vinblastina/análogos & derivados , VinorelbinaRESUMEN
Chemosensitivity of the human colon carcinoma HCT-15 cell line to 4'-epidoxorubicin proved to be 100-fold higher than that of its variant HCT-15 EDR. Confocal scanning microscopy showed significant less drug accumulation in HCT-15 EDR. A 2-fold increase in hsp27 expression was found in HCT-15 EDR, with no alteration in hsp70. The expression of the drug exporter Pgp was similar in both cell lines, despite the lower drug accumulation shown by HCT-15 EDR in respect to HCT-15. Other molecules implicated in the acquisition of enhanced chemoresistance or a more active Pgp variant present in HCT-15 EDR, could explain the phenomenon.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Antibióticos Antineoplásicos/farmacología , Epirrubicina/farmacología , Proteínas de Choque Térmico , Antibióticos Antineoplásicos/metabolismo , Western Blotting , Supervivencia Celular , Neoplasias del Colon , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Epirrubicina/metabolismo , Proteínas de Choque Térmico HSP27 , Proteínas HSP70 de Choque Térmico/análisis , Humanos , Inmunohistoquímica , Chaperonas Moleculares , Proteínas de Neoplasias/análisis , Células Tumorales CultivadasRESUMEN
We have previously reported the antimetastatic effect of a single low-dose of cyclophosphamide (Cy) on L-TACB rat lymphoma. The phenomenon could be adoptively transferred in immunocompetent rats and is abolished in nude mice, facts for which an immunomodulatory explanation was proposed. The aim of this paper was to identify the mechanism(s) by which spleen cells from Cy-treated tumour-bearing rats could exert this antimetastatic activity. Conditioned media obtained by incubation of spleen cells from Cy-treated and non-treated tumour-bearing rats, under specific or non-specific stimulation, were assayed to evaluate their effect on lymphocyte proliferation. The production of transforming growth factor beta (TGF-beta), interleukin-10 (IL-10) and nitric oxide (NO) by conditioned media was also studied. The restoration of spleen lymphoproliferative responses to normal levels when exposed to media conditioned by splenocytes from Cy-treated tumour-bearing rats, together with a decreased production of suppressive cytokines TGF-beta, IL-10 and NO, suggest an enhancement of host antimetastatic immunity triggered by single low-dose Cy treatment.
Asunto(s)
Antineoplásicos Alquilantes/administración & dosificación , Ciclofosfamida/administración & dosificación , Inmunosupresores/administración & dosificación , Linfoma/prevención & control , Metástasis de la Neoplasia/prevención & control , Animales , División Celular , Femenino , Interleucina-10/análisis , Linfoma/patología , Masculino , Metástasis de la Neoplasia/patología , Nitritos/análisis , Ratas , Factor de Crecimiento Transformador alfa/análisisRESUMEN
The HMGCoA reductase inhibitor Lovastatin (LOV) has previously shown to abrogate p21ras farnesylation, which is associated with invasive and metastatic abilities in many tumor models. Considering the scarcity of therapeutic resources against metastasis, our objective was to study LOV as an antimetastatic agent on L-TACB rat lymphoma, which as a syngeneic tumor model resembles more closely the situation in human cancer. We also aimed to analyze the effect of LOV on chemoinvasion, motility, metalloproteases secretion, angiogenic capacity, and adhesion to the reconstituted basement membrane Matrigel. Our results showed that LOV caused no effect on cell motility, metalloprotease secretion and neovascularization. Conversely, LOV produced a significant inhibition of invasiveness, which could be a consequence of an impaired cell adhesion to the basement membrane observed. These effects could explain, at least in part, the inhibitory action of LOV on L-TACB rat lymphoma metastases.
Asunto(s)
Antineoplásicos/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Lovastatina/uso terapéutico , Linfoma/tratamiento farmacológico , Animales , Movimiento Celular/efectos de los fármacos , Colesterol/sangre , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Linfoma/patología , Masculino , Invasividad Neoplásica , Neovascularización Patológica , Ratas , Células Tumorales CultivadasRESUMEN
Concomitant resistance (CR), the phenomenon by which tumor-bearing hosts are able to inhibit secondary implants of the same tumor at distant sites of the body, has been previously observed by us and others in different murine tumor models. Here, we verified the generation of CR in nude mice by tumors induced by SC inoculation of Calu-6, a human lung carcinoma cell line. Histological analysis of secondary tumors subject to CR did not reveal macrophage infiltration nor cytotoxic signs. Although serum from tumor-bearing mice inhibited in vitro [3H]thymidine uptake by Calu-6 cells, no significant differences in [3H]thymidine labeling index of tumors implanted in the right flank of mice with and without a primary tumor in the left flank were detected. In our model, the presence of a primary tumor hindered remote tumor angiogenesis, as well as serum from tumor-bearing mice inhibited in vitro proliferation of an endothelial cell line derived from a murine hemangioendothelioma. Conversely, an enhancement of the apoptotic index was observed in secondary tumor implants carried out in tumor-bearing mice. The results reported herein show that human tumor cells are capable of inducing CR, and that this phenomenon would be a consequence of an impaired neovascularization as well as an increased programmed cell death at sites distant from the primary tumor.
Asunto(s)
Apoptosis , Neoplasias Pulmonares/patología , Neovascularización Patológica , Animales , División Celular , Línea Celular , ADN de Neoplasias/biosíntesis , Humanos , Inmunidad Innata , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/irrigación sanguínea , Masculino , Ratones , Ratones Desnudos , Índice Mitótico , Metástasis de la Neoplasia , Timidina/metabolismo , Células Tumorales CultivadasRESUMEN
The aim of this paper was to identify the mechanism/s responsible of the antimetastatic effect of a single low dose of cyclophosphamide (Cy), previously demonstrated by us in the rat lymphoma LTACB. No direct cytotoxic antimetastatic activity of Cy could be proved. In vitro treatment of L-TACB cells with mafosfamide did not alter their invasiveness or their motility. The adoptive transfer of splenocytes from Cy-treated tumor-bearing rats, together with L-TACB cells inhibited their metastatic growth. The single low dose Cy treatment of T-immunodeficient nude mice did not show the antimetastatic effect on L-TACB observed in immunocompetent mice. An inhibition of the metastatic ability due to immunomodulation by Cy is proposed.
Asunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Ciclofosfamida/uso terapéutico , Linfoma/patología , Linfoma/terapia , Metástasis de la Neoplasia/prevención & control , Traslado Adoptivo , Animales , Antineoplásicos Alquilantes/administración & dosificación , Movimiento Celular/efectos de los fármacos , Ciclofosfamida/administración & dosificación , Ciclofosfamida/análogos & derivados , Ciclofosfamida/farmacología , Esquema de Medicación , Femenino , Transfusión de Linfocitos , Linfoma/tratamiento farmacológico , Masculino , Ratones , Ratones Desnudos , Invasividad Neoplásica , Ratas , Ratas Endogámicas , Bazo/inmunología , EsplenectomíaRESUMEN
OBJECTIVES: To ascertain intravesical vinorelbine tartrate (VNR) antitumor activity against MB-49, a murine transitional cell carcinoma of the bladder (TCC), in an in vivo setting. MATERIALS AND METHODS: C57B1/6J female mice were intravesically implanted with 5 x 10(4) MB-49 cells and treated locally with VNR. Tumor incidence and volume analyses, as well as survival studies were carried out. RESULTS: Tumor incidence was significantly lower in VNR-treated mice (48%, n = 23) than in controls (84%, n = 19), as evaluated sixteen days after MB-49 orthotopic inoculation. Intravesical tumor volume was also significantly smaller in treated mice respect to controls (median [range]: 0.5 [0.4 to 61.8] mm.3 versus 47.7 [4.2 to 179.7] mm.3 respectively, p < 0.001 Kruskal-Wallis test). Median survival duration of the animals treated with VNR was 68 [21 to 68] days, and was significantly greater (p = 0.01, Kruskal-Wallis test) than that of untreated controls (18 [16 to 20] days). CONCLUSION: Intravesical VNR treatment demonstrated an evident antitumor effect against the TCC model assayed. The results obtained suggest a potential use of VNR as intravesical treatment for superficial TCC following transurethral bladder tumor resection to prevent recurrence or retard tumor growth.
Asunto(s)
Antineoplásicos Fitogénicos/administración & dosificación , Carcinoma de Células Transicionales/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Vinblastina/análogos & derivados , Administración Intravesical , Animales , Carcinoma de Células Transicionales/mortalidad , Femenino , Ratones , Ratones Endogámicos C57BL , Trasplante de Neoplasias , Neoplasias de la Vejiga Urinaria/mortalidad , Vinblastina/administración & dosificación , VinorelbinaRESUMEN
PURPOSE: To study the effect of vinorelbine (VNR) on in vitro cell proliferation, invasiveness, cell adhesion to substrate, cell motility and metalloproteinase secretion of MB-49, a murine transitional cell carcinoma of the bladder (TCC). MATERIALS AND METHODS: The colorimetric MTS assay, which depends upon viable versus nonviable mitochondria, was used to evaluate the effect of graded concentrations of VNR on in vitro MB-49 cell growth. Chemoinvasion and cell motility were studied in TCC cells exposed for 24 hours to a noncytotoxic dose of VNR, through their ability to migrate across Matrigel-coated or Type IV collagen-coated 8-microns. pore filters. Zymographic studies in gelatin-embedded polyacrylamide gels were done to investigate gelatinolytic activity in conditioned media from treated and untreated MB-49 cells. RESULTS: Vinorelbine inhibited MB-49 cell growth in a dose-dependent manner (IC(50)40 ng./ml.). In vitro cell invasive capacity of MB-49 cells pretreated for 24 hours with VNR at noncytotoxic doses (1 and 10 ng./ml.) was significantly lower than that of untreated cells. The decreased invasion of VNR-treated cells was not accompanied by a diminished adhesion to Matrigel or type IV collagen nor by a significant reduced secretion of gelatinolytic metalloproteinases. Instead, motility of MB-49 cells exposed to noncytotoxic concentrations of VNR was inhibited in a dose-response fashion similar to that of invasion. CONCLUSION: Vinorelbine proved to be an effective drug to inhibit tumor cell growth and invasion in a transitional cell bladder carcinoma model. The results obtained would justify preclinical studies to evaluate the effectiveness of VNR as a potential treatment of TCC.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Carcinoma de Células Transicionales/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Vinblastina/análogos & derivados , Animales , Antineoplásicos Fitogénicos/uso terapéutico , Carcinoma de Células Transicionales/patología , Adhesión Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Metaloendopeptidasas/efectos de los fármacos , Metaloendopeptidasas/metabolismo , Invasividad Neoplásica , Células Tumorales Cultivadas , Neoplasias de la Vejiga Urinaria/patología , Vinblastina/farmacología , Vinblastina/uso terapéutico , VinorelbinaRESUMEN
Twelve immortalized human cell lines derived from primary or metastatic lesions from pancreatic carcinomas were studied with respect to their in vitro invasiveness and motility. Various levels of invasive capacity and chemotactic responses were found. Zymograms of cells conditioned media were carried out to determine the role of metalloproteinases in pancreatic cancer invasion. No correlations were found, however, between invasive capacity of pancreatic carcinoma cell lines and gelatinase secretion. Putative reasons for these findings are discussed.
Asunto(s)
Gelatinasas/metabolismo , Metaloendopeptidasas/fisiología , Neoplasias Pancreáticas/metabolismo , Movimiento Celular , Humanos , Invasividad Neoplásica , Neoplasias Pancreáticas/patología , Células Tumorales Cultivadas/fisiologíaRESUMEN
Twelve immortalized human cell lines derived from primary or metastatic lesions from pancreatic carcinomas were studied with respect to their in vitro invasiveness and motility. Various levels of invasive capacity and chemotactic responses were found. Zymograms of cells conditioned media were carried out to determine the role of metalloproteinases in pancreatic cancer invasion. No correlations were found, however, between invasive capacity of pancreatic carcinoma cell lines and gelatinase secretion. Putative reasons for these findings are discussed.
RESUMEN
Matrigel, a reconstituted extract of basement membrane, enhances the growth of different human cancer cell lines when transplanted into nude mice. Here that stimulation was confirmed in the BALB/c murine mammary-tumor cell line M3MC, as well as in human colon (SW948) and mammary (MDA-MB-468) carcinoma cell lines transplanted in nude and SCID mice, respectively. Subcutaneous and intra-mammary fat-pad inoculations of Matrigel alone generated an angiogenic response which was macroscopically evident by day 9. Histological analysis of the local host reaction occurring at the site of injection revealed an early peripheral fibroblast response, followed by mononuclear cell infiltration, solid and hollow fibroblast cords projections from the edge to the center of the Matrigel plug, and finally capillary ingrowths. Conditioned media obtained from the gels generated in vivo, acted as very strong chemoattractants for mouse lung capillary endothelial cells, stimulating their motility between 38 and 82 times with respect to the control. Our results suggest an important role of host cells recruited by Matrigel, which could favor angiogenesis of the area and thus facilitate the growth of tumor cells co-inoculated with the basement membrane extract.
Asunto(s)
Colágeno/toxicidad , Laminina/toxicidad , Neoplasias Experimentales/irrigación sanguínea , Neoplasias/irrigación sanguínea , Neovascularización Patológica , Proteoglicanos/toxicidad , Adenocarcinoma/irrigación sanguínea , Adenocarcinoma/enzimología , Adenocarcinoma/patología , Animales , Neoplasias de la Mama/irrigación sanguínea , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/patología , División Celular/efectos de los fármacos , Quimiotaxis/efectos de los fármacos , Colágeno/metabolismo , Colagenasas/metabolismo , Neoplasias del Colon/irrigación sanguínea , Neoplasias del Colon/enzimología , Neoplasias del Colon/patología , Combinación de Medicamentos , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Femenino , Humanos , Neoplasias Mamarias Experimentales/irrigación sanguínea , Neoplasias Mamarias Experimentales/enzimología , Neoplasias Mamarias Experimentales/patología , Metaloproteinasa 9 de la Matriz , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Trasplante de Neoplasias , Neoplasias/enzimología , Neoplasias/patología , Neoplasias Experimentales/enzimología , Neoplasias Experimentales/patología , Estimulación Química , Células Tumorales CultivadasRESUMEN
We have previously observed that acellular extracts from necrotic areas (NE) of the non-metastatic murine mammary adenocarcinoma M3, enhance in vitro cell detachment and spontaneous lung metastases. In the present study, using different proteinase inhibitors along with NE, only the calcium chelator EDTA could significantly abrogate the enhanced cell detachment from M3 produced by NE. The typical cleavage products of type IV collagenase were detected inside the tumor necrotic area, mainly in association with necrobiotic cells, as evaluated by Western blot analysis and immunohistochemical assays. Zymography revealed the presence of 72- and 92-kDa gelatinase/type IV collagenase in NE. Moreover, NE increased the in vitro invasive ability of cultured M3 cells. The use of specific antibodies against both 72- and 92-kDa type IV collagenases in the invasion assay showed that only the latter was able to revert the enhanced invasiveness to the baseline. It can be concluded that tumor necrosis is an important source of gelatinase/type IV collagenase, mainly in its 92 kDa form, and plays a major role in tumor invasion.
Asunto(s)
Colagenasa Microbiana/análisis , Invasividad Neoplásica , Neoplasias Experimentales/patología , Pepsina A/análisis , Animales , Adhesión Celular/efectos de los fármacos , Colágeno/metabolismo , Matriz Extracelular/metabolismo , Femenino , Gelatinasas , Ratones , Ratones Endogámicos BALB C , Necrosis , Neoplasias Experimentales/enzimología , Inhibidores de Proteasas/farmacologíaRESUMEN
Serum from mice bearing five weakly immunogenic or nonimmunogenic tumors inducing concomitant resistance exhibited a growth-inhibitory activity on in vitro proliferation of the tumor cells. This activity was proportional to the intensity of concomitant resistance and correlated with the capacity to restrain metastatic development. It was not attributable to cytotoxic antibodies, was relatively nonspecific, and operated through a cytostatic and reversible mechanism. All attempts to transfer antitumor resistance in vivo by serum inoculation have failed, but this could be attained by parabiosis. Physical and chemical serum treatments suggest that heat-, acid-, and alkali-resistant peptide(s) with molecular weights ranging from 1000 to 3000 could account for this inhibitory effect.
Asunto(s)
Anticuerpos Antineoplásicos/inmunología , Neoplasias Experimentales/inmunología , Animales , División Celular , Citotoxicidad Inmunológica , Femenino , Masculino , Ratones , Ratones Endogámicos , Neoplasias Experimentales/sangre , Neoplasias Experimentales/patología , Factores de TiempoRESUMEN
Se entiende por inunidad concomitante (IC) la falta de desarrollo de un segundo implante tumoral distante del primario, atribuyéndole una explicación inmunológica. El objeto de estos trabajos fue estudiar la IC asociada a tumores espontáneos. En ratones BALB/c, se comprobó que el transplante de varios tumores singenecicos, de indetectable inmunogenicidad, inhibían el desarrollo de un segundo implante del mismo tumor, y a veces de otro tumor, evidenciándose cierta inespecificidad. Esta IC se observada también en ratones atímicos, jóvenes y adultos, y en los tratados con sílica, descartándose la participación de linfocitos T, células NK y macrófagos. La falta de desarrollo del implante secundario no se debía a rechazo tumoral, contrariamente a lo que pudimos observar con un tumor inmunogénico en un sistema alogeneico, sino a citostasis. Este estado de tumor dormido se debería a la falta de aflujo de células del huésped, ya que cualquier estimulo inflamatorio local abrogaba la IC llevando a un rápido crecimiento tumoral. Estaría en juego un fenómeno de anti-inflamación ya que se comprobó que un foco inflamatorio inhibía el desarrollo de un implante tumoral en el flanco contralateral, que el mismo efecto se conseguía con la administración de piroxicam, y que el propio tumor disminuía la reacción inflamatoria creada por la implantación de un cuerpo extraño. Considerando a las metástasis como implantes secundarios naturales, se compararon dos tumores de mama de origen común, pero diferente... (AU)
Asunto(s)
Ratones , Animales , Neoplasias Experimentales/inmunología , Inmunidad Innata , Linfocitos T/fisiología , Ratones Endogámicos BALB CRESUMEN
Se entiende por inunidad concomitante (IC) la falta de desarrollo de un segundo implante tumoral distante del primario, atribuyéndole una explicación inmunológica. El objeto de estos trabajos fue estudiar la IC asociada a tumores espontáneos. En ratones BALB/c, se comprobó que el transplante de varios tumores singenecicos, de indetectable inmunogenicidad, inhibían el desarrollo de un segundo implante del mismo tumor, y a veces de otro tumor, evidenciándose cierta inespecificidad. Esta IC se observada también en ratones atímicos, jóvenes y adultos, y en los tratados con sílica, descartándose la participación de linfocitos T, células NK y macrófagos. La falta de desarrollo del implante secundario no se debía a rechazo tumoral, contrariamente a lo que pudimos observar con un tumor inmunogénico en un sistema alogeneico, sino a citostasis. Este estado de tumor dormido se debería a la falta de aflujo de células del huésped, ya que cualquier estimulo inflamatorio local abrogaba la IC llevando a un rápido crecimiento tumoral. Estaría en juego un fenómeno de anti-inflamación ya que se comprobó que un foco inflamatorio inhibía el desarrollo de un implante tumoral en el flanco contralateral, que el mismo efecto se conseguía con la administración de piroxicam, y que el propio tumor disminuía la reacción inflamatoria creada por la implantación de un cuerpo extraño. Considerando a las metástasis como implantes secundarios naturales, se compararon dos tumores de mama de origen común, pero diferente...
Asunto(s)
Ratones , Animales , Inmunidad Innata , Neoplasias Experimentales/inmunología , Linfocitos T/fisiología , Ratones Endogámicos BALB CRESUMEN
Concomitant immunity (CI) is defined as the lack or retardation or proliferation of a secondary tumor implant at a distant site; it has been given an immunological interpretation. Our experiments were designed to investigate CI in association with spontaneous tumors with or without metastases. In BALB/c mice, various syngeneic tumors, of undetectable immunogenicity, induced CI, preventing the development of a secondary implant of the same and occasionally of another tumor, indicating some degree of nonspecificity. This CI could also be observed in young and adult nude mice with high and low NK level, and in those treated with silica, discarding and participation of T lymphocytes, NK cells and macrophages, respectively. The lack of development of the secondary implant was not due to tumor rejection--contrarily to observations in allogeneic systems with immunogenic tumor--but to cytostasis. This "dormant tumor" state is observed together with the absence of host cell infiltration. The creation of a local inflammatory reaction abrogated CI, resulting in rapid tumor growth. On the other hand, an inflammatory reaction created by a foreign body inhibited the development of a tumor implant in the contralateral flank and tumor growth could be inhibited by piroxicam; furthermore, the tumor itself diminished the inflammatory reaction created by a foreign body at a distant site. Considering metastases as natural secondary implants, two mammary adenocarcinomas with a common origin were compared, one with 0 and the other with 100% metastatic incidence. The non-metastatic tumor induced stronger and earlier CI against both tumors and prevented the development of experimental and spontaneous metastases; moreover; its surgical extirpation led to the appearance of lung metastases.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Tolerancia Inmunológica/inmunología , Metástasis de la Neoplasia/inmunología , Neoplasias Experimentales/inmunología , Linfocitos T/fisiología , Animales , Inmunidad Innata , Ratones , Ratones Endogámicos BALB C , Ratones DesnudosRESUMEN
Concomitant immunity (CI) is defined as the lack or retardation or proliferation of a secondary tumor implant at a distant site; it has been given an immunological interpretation. Our experiments were designed to investigate CI in association with spontaneous tumors with or without metastases. In BALB/c mice, various syngeneic tumors, of undetectable immunogenicity, induced CI, preventing the development of a secondary implant of the same and occasionally of another tumor, indicating some degree of nonspecificity. This CI could also be observed in young and adult nude mice with high and low NK level, and in those treated with silica, discarding and participation of T lymphocytes, NK cells and macrophages, respectively. The lack of development of the secondary implant was not due to tumor rejection--contrarily to observations in allogeneic systems with immunogenic tumor--but to cytostasis. This [quot ]dormant tumor[quot ] state is observed together with the absence of host cell infiltration. The creation of a local inflammatory reaction abrogated CI, resulting in rapid tumor growth. On the other hand, an inflammatory reaction created by a foreign body inhibited the development of a tumor implant in the contralateral flank and tumor growth could be inhibited by piroxicam; furthermore, the tumor itself diminished the inflammatory reaction created by a foreign body at a distant site. Considering metastases as natural secondary implants, two mammary adenocarcinomas with a common origin were compared, one with 0 and the other with 100
metastatic incidence. The non-metastatic tumor induced stronger and earlier CI against both tumors and prevented the development of experimental and spontaneous metastases; moreover; its surgical extirpation led to the appearance of lung metastases.(ABSTRACT TRUNCATED AT 250 WORDS)
RESUMEN
An attempt was made to explain the distinct lung metastatic patterns of 2 mammary adenocarcinomas with a common BALB/c origin: M3, which does not induce spontaneous metastases, and MM3 with an almost 100% incidence. No difference between the 2 tumors was detected with respect to host mononuclear cell content, degree of immunogenicity or lung-colony-forming ability. Conversely, there was a marked difference in the capacity to induce concomitant resistance: M3-bearing mice induced stronger and earlier resistance against i.v. challenge of both M3 and MM3 tumor cells than MM3-bearing mice; this resistance was expressed as lower number of lung metastases and lower tumor-cell proliferation in metastatic nodules. M3 was also able to control the development of spontaneous metastases: metastases developed in all M3-excised mice, compared with none in M3-bearing mice, while MM3-bearing mice also bearing a secondary M3 tumor developed fewer metastases than mice bearing MM3 only. This anti-metastatic effect does not appear to depend on classical immunological mechanisms since no difference could be detected between the 2 tumors in response to T cells, NK, macrophages or antibodies.