RESUMEN

PURPOSE: To evaluate the activity and toxicity of the combination of paclitaxel given by three-hour infusion, and carboplatin as first-line chemotherapy in patients with advanced breast cancer (ABC). BACKGROUND: Paclitaxel is an active agent in ABC. Furthermore, our group has shown that the combination of paclitaxel and carboplatin is effective in anthracycline-resistant ABC. PATIENTS AND METHODS: From January 1996 until March 1997, 66 women with ABC were treated with paclitaxel (175 mg/m2) by three-hour infusion followed by carboplatin at an AUC of 6 mg x min/ml every three weeks. The median age of the patients was 56 years (range 28-75). A total of 39 patients had received adjuvant chemotherapy and 22 of them were treated with an anthracycline or mitoxantrone-containing regimen. RESULTS: A total of 324 cycles (median: six) were administered, 273 (85%) of them at full dose. The median number of delivered cycles was six. The median delivered dose intensity (DI) of paclitaxel was 55.1 mg/m2/week (range 30.5-69.3) and the relative DI was 0.95 (range 0.5-1.2). Eight patients (12%, 95% confidence interval (CI): 5%-22%) achieved complete and 28 (42%, 95% CI: 30%-55%) partial responses. Grade 3-4 toxicities included anemia (5%), granulocytopenia (24%), thrombocytopenia, nausea/vomiting and allergic reaction (3% each), myalgias/arthralgias and neurotoxicity (1.5% each). Febrile neutropenia occurred in eight (12%) patients. Alopecia was universal. After a median follow-up of 17.3 (range 0.07-24.5) months, 48 (72%) patients have demonstrated tumor progression and 24 (36%) have died. Median time to progression was 8.6 (range 0.07-23+) months and median survival 20.4 (range 0.07-24.5+) months. CONCLUSIONS: The combination of paclitaxel and carboplatin has moderate activity in ABC and can be easily delivered on an outpatient basis with manageable toxicity. This regimen may be useful especially in patients to whom anthracyclines or cisplatin administration is precluded because of other concomitant diseases.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Carboplatino/uso terapéutico , Paclitaxel/uso terapéutico , Adulto , Anciano , Antineoplásicos Fitogénicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carboplatino/administración & dosificación , Femenino , Humanos , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Resultado del Tratamiento

RESUMEN

Placenta growth factor (PlGF) is a homodimeric glycoprotein, 46-50 kDa in size, belonging to the vascular endothelial growth factor (VEGF) sub-family. It exists as two isoforms, PlGF-1 and -2, the latter having a heparin-binding domain. Like VEGF, it is a potent angiogenic factor; however, PlGF homodimers interact with the VEGF receptor Flt-1 (fms-like tyrosine kinase), but not with the kinase domain-containing region (KDR). Since PlGF is made by the human placenta and extravillous trophoblast (EV-T) cells of the human placenta express Flt-1 in situ, these cells may be responsive to PlGF. Therefore, this study examined whether first trimester EVT cells propagated in vitro expressed the mRNA or the protein of Flt-1 and PlGF, and whether exogenous PlGF-1 had any effect on EVT cell proliferation, migration or invasiveness. Immunocytochemical and RT-PCR analyses revealed that both normal and SV40 Tag-immortalized EVT cells expressed the protein and mRNA for Flt-1, but not for PlGF-1 or -2. Exogenous PlGF-1 stimulated proliferation (measured by 3H-thymidine uptake) of normal EVT cells in a concentration-dependent manner, but only in the presence of excess heparan sulphate proteoglycans (HSPGs). These results raise two possibilities: that exogenous PlGF-1 (in spite of having a low affinity for heparin) was sequestered away from its receptor because of binding to heparan sulphate proteoglycans on the EVT cell surface or the ECM, or that HSPGs could modify the interaction between Flt-1 and PlGF. PlGF-1, in the presence or absence of HSPGs, however, had no effect on EVT migration or invasiveness, when measured with a transwell invasion (in the presence of Matrigel) or migration (in the absence of Matrigel) assay. These findings place PlGF amongst a large group of growth factors that promote EVT cell proliferation without influencing their migratory or invasive behaviours, and suggest that PlGF-Flt-1 interactions may be regulated by HSPGs in situ.

Asunto(s)

Inductores de la Angiogénesis/fisiología , Proteínas Gestacionales/fisiología , Trofoblastos/citología , Adulto , Inductores de la Angiogénesis/farmacología , División Celular/efectos de los fármacos , División Celular/fisiología , Línea Celular , Movimiento Celular/efectos de los fármacos , Movimiento Celular/fisiología , Cartilla de ADN/química , Femenino , Técnica del Anticuerpo Fluorescente Indirecta , Proteoglicanos de Heparán Sulfato/farmacología , Humanos , Factor de Crecimiento Placentario , Embarazo , Proteínas Gestacionales/farmacología , Primer Trimestre del Embarazo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , ARN Mensajero/metabolismo , Proteínas Tirosina Quinasas Receptoras/genética , Proteínas Tirosina Quinasas Receptoras/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Trofoblastos/efectos de los fármacos , Trofoblastos/metabolismo , Receptor 1 de Factores de Crecimiento Endotelial Vascular

RESUMEN

Vascular endothelial growth factor (VEGF) is a homodimeric glycoprotein that promotes angiogenesis and vascular hyperpermeability and interacts with two receptors, fms-like tyrosine kinase (Flt-1) and kinase domain-containing region (KDR). In situ localization in the pregnant human uterus revealed that VEGF mRNA is expressed primarily by the maternal decidua, whereas the receptor Flt-1 is expressed primarily by chorionic vascular endothelium and trophoblast cells-in particular, the extravillous trophoblast (EVT). We examined whether the mRNA and protein of VEGF and its receptors are expressed by invasive human first-trimester EVT cells propagated in culture and whether VEGF influences EVT cell proliferation, migration, and invasiveness. Proliferation was assessed by the uptake of [3H]thymidine. Invasion and migration across transwells were assessed by the degree of cellular transgression of a Millipore membrane coated, respectively, with and without Matrigel. Results of immunocytochemical and reverse transcription-polymerase chain reaction analysis revealed that both protein and mRNA of VEGF, Flt-1, and KDR were expressed by cultured normal EVT cells as well as their premalignant derivative produced by SV-40 Tag-immortalization, and BeWo choriocarcinoma cells. Under serum-free conditions, exogenous VEGF121 (the non-heparin-binding isoform) stimulated proliferation of all three cell lines in a concentration-dependent manner. The effects were abolished with a VEGF-neutralizing antibody. The same stimulatory effects on EVT cells were also seen with exogenous VEGF165 (a heparin-binding isoform), only after a cleaving of the heparin-binding domain with plasmin or a blocking of heparin binding sites with excess soluble heparan sulphate proteoglycans (HSPGs), suggesting a regulatory role of HSPGs. However, VEGF121 and VEGF165 (with and without the HSPG pretreatment) had no effect on normal EVT cell migration or invasiveness. Thus, VEGF may provide a dual role in angiogenesis and EVT cell proliferation during normal placental development.

Asunto(s)

Factores de Crecimiento Endotelial/farmacología , Linfocinas/farmacología , Trofoblastos/fisiología , División Celular , Decidua/química , Femenino , Expresión Génica , Humanos , Inmunohistoquímica , Reacción en Cadena de la Polimerasa , Embarazo , Proteínas Proto-Oncogénicas/genética , ARN Mensajero/análisis , ADN Polimerasa Dirigida por ARN , Proteínas Tirosina Quinasas Receptoras/genética , Receptores de Factores de Crecimiento/genética , Receptores de Factores de Crecimiento Endotelial Vascular , Factor A de Crecimiento Endotelial Vascular , Receptor 1 de Factores de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial Vascular

RESUMEN

In a phase II study, 66 patients with advanced breast cancer (median age 56 years; range, 28 to 75 years) were treated with paclitaxel (Taxol), 175 mg/m2 infused over 3 hours, and carboplatin (Paraplatin), dosed to attain an area under the concentration-time curve (AUC) of 6 mg x min/mL; treatment was repeated every 3 weeks. A total of 38 (58%) patients had received prior adjuvant chemotherapy, 21 with a regimen containing an anthracycline or mitoxantrone (Novantrone). As of May 1997, 295 cycles of paclitaxel-carboplatin have been administered, 248 (84%) at full dose. The relative dose intensity of paclitaxel is 0.9 (range, 0.5 to 1.2). Of the 66 patients, 8 (12%) have achieved a complete response and 27 (41%) a partial response, for a total response rate of 53%. Grade 3 to 4 toxicities have included anemia (5%), leukopenia (25%), thrombocytopenia (5%), nausea/vomiting (7%), myalgias/arthralgias (4%), allergic reaction, neurotoxicity, and infection (2% each). Alopecia has been universal. Median time to progression is 8.9 months; median survival has not yet been reached. We conclude that the combination of paclitaxel and carboplatin has significant activity in advanced breast cancer and can easily be administered on an outpatient basis with manageable toxicity.

Asunto(s)

Antineoplásicos Fitogénicos/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Carboplatino/uso terapéutico , Paclitaxel/uso terapéutico , Adulto , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos Fitogénicos/efectos adversos , Carboplatino/efectos adversos , Quimioterapia Combinada , Femenino , Humanos , Persona de Mediana Edad , Paclitaxel/efectos adversos

RESUMEN

BACKGROUND: Paclitaxel has been demonstrated to have significant activity in recurrent or metastatic head and neck cancer (HNC). In addition, the combination of paclitaxel and cisplatin is active in untreated patients with inoperable HNC. Substitution of carboplatin for cisplatin allows the treatment to be delivered on an outpatient basis. PURPOSE OF THE STUDY: To evaluate the activity and toxicity of the combination of paclitaxel by three-hour infusion and carboplatin as first-line chemotherapy in patients with recurrent or metastatic HNC. PATIENTS AND METHODS: From March 1994 until August 1996, 49 patients with recurrent or metastatic HNC were treated with paclitaxel (200 mg/m2, by three-hour infusion) followed by carboplatin at an AUC of 7 mg.min/ml, every four weeks. G-CSF was administered prophylactically on days 2 to 12 of each cycle. There were 41 men and 8 women with a median age of 57 years (range 23-73). The majority of the patients were symptomatic and they had recurrent disease locoregionally. Fourteen patients had nasopharyngeal cancer (NPC) and 35 had squamous cell cancers of other areas of the head and neck region (non-NPC). RESULTS: At the completion of treatment, two patients with NPC demonstrated complete and six partial responses for an overall response rate of 57% (95% CI 29%-82%). Among patients with non-NPC, the response rate was 23% (95% CI 9%-37%). After a median follow up period of 15 months, the median time to progression was 4.3 months in the non-NPC group and 16.5 months in the NPC group. At the time of the analysis, median survival had not been reached in NPC while it was 7.3 months in non-NPC patients. Grade 3-4 toxicities included anemia (2%) and leukopenia, thrombocytopenia, stomatitis, nausea/vomiting and diarrhea (4% each). CONCLUSIONS: The combination of paclitaxel and carboplatin appears to be well tolerated but only moderately active in patients with advanced non-NPC of the head and neck region. However, its activity appears promising in NPC and deserves further investigation.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias Nasofaríngeas/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Paclitaxel/administración & dosificación

RESUMEN

Paclitaxel was administered at a dose of 175 mg/m2 in a 3-hour infusion every 3 weeks in platinum pretreated patients with ovarian cancer. 51 patients with a median age of 57 years entered the study. 33 (65%) presented with stage III and 18 (35%) with stage IV disease. 39 patients (76%) were previously treated with only one and 12 (24%) with two regimens. The median interval from the last previous chemotherapy was 4 months (range, 1-65). Ninety-eight per cent of the planned dose of paclitaxel was actually delivered. Overall and complete response rate was 26% (13/51) and 16% (8/51), respectively. All complete responses were observed among patients previously treated with only one regimen. Median time to progression was 10.26 months (range, 4.9-25.2+) and median survival 15.6 months (range, 1.3-27.1+). Factors influencing survival were performance status and the number of previous regimens.

Asunto(s)

Antineoplásicos Fitogénicos/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Paclitaxel/uso terapéutico , Compuestos de Platino/uso terapéutico , Adulto , Anciano , Antineoplásicos Fitogénicos/efectos adversos , Resistencia a Antineoplásicos , Femenino , Humanos , Persona de Mediana Edad , Paclitaxel/efectos adversos , Cooperación del Paciente , Tasa de Supervivencia , Resultado del Tratamiento

RESUMEN

PURPOSE: To evaluate the impact on the response rate in patients with advanced breast cancer (ABC) of the doubling of the dose intensity (DI) of epirubicin monotherapy. PATIENTS AND METHODS: From January 1991 until April 1996, 167 patients with ABC were randomized to receive epirubicin (110 mg/m2) either every four (81 patients, group A) or every two weeks (86 patients, group B). Filgrastim (5 micrograms/kg/daily) was administered prophylactically on days 2-12 of each cycle. RESULTS: The two groups were equally balanced in terms of major patient and tumor characteristics. Even though the median cumulative dose of epirubicin was identical in the two groups (651 mg/m2), the median DI of epirubicin was doubled in group B (27.2 vs. 52.9 mg/m2/wk, respectively). The complete response (CR) rate was significantly increased in group B (5%, 95% CI: 0.16%-9.84% vs. 17%, 95% CI: 8.9%-25.08%, P = 0.011), although overall response rates were similar (49% vs. 53%, P = 0.5957). Also, there was no significant difference in the incidence of grade 3-4 toxicity between the two groups. After a median follow-up of 25 months (range, 0.43-43.3+) no significant difference was observed in the duration of response (median, 10 months vs. 8.5 months, P = 0.5130), time to progression (median, 7.2 months vs. 7.4 months, P = 0.2970) or survival (median, 14.6 months vs. 14.9 months, P = 0.4483). Logistic regression analysis showed that performance status was a significant variable for response (P = 0.0068) and multivariate analysis using the Cox proportional hazards model revealed that performance status was significant for survival (P = 0.0049), while the presence of multiple metastases (P = 0.0020) was significant for time to progression. CONCLUSION: Doubling the planned DI of epirubicin monotherapy significantly increases the CR rate but has no influence on time to progression or survival in patients with ABC.

Asunto(s)

Antibióticos Antineoplásicos/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Epirrubicina/administración & dosificación , Adulto , Anciano , Antibióticos Antineoplásicos/efectos adversos , Supervivencia sin Enfermedad , Esquema de Medicación , Epirrubicina/efectos adversos , Femenino , Humanos , Persona de Mediana Edad , Análisis de Supervivencia , Resultado del Tratamiento

RESUMEN

We performed a phase II study to evaluate the activity and toxicity of the combination of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and carboplatin as first-line treatment in patients with recurrent or metastatic head and neck cancer. From March 1994 until August 1996, 49 patients were treated with paclitaxel 200 mg/m2 by 3-hour infusion followed by carboplatin at an area under the concentration-time curve of 7 mg/mL x min; treatment was requested every 4 weeks. Granulocyte colony-stimulating factor was administered prophylactically on days 2 to 12 of each cycle. The study included 41 men and eight women, with a median age of 57 years (range, 23 to 73 years). Most of the patients were symptomatic and had locoregional disease. Primary sites included nasopharynx (14 patients), oropharynx (six), oral cavity (four), hypopharynx (three), larynx (20), paranasal sinuses (one), and unknown (one). After the completion of treatment, four patients (8%; 95% confidence interval, 0% to 16%) achieved a complete response and 12 (24%; 95% confidence interval, 12% to 37%) achieved a partial response. Grade 3/4 toxicities included anemia (2%) and leukopenia, thrombocytopenia, nausea/vomiting, diarrhea, and stomatitis (4% each). After a median follow-up of 15.3 months, median time to progression was 5.7 months (range, 0.5 to 29.8+ months) and median survival was 13.3 months (range, 0.5 to 30.2+ months). In our ongoing study in a similar patient population, gemcitabine was substituted for carboplatin.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Adulto , Anciano , Alopecia/inducido químicamente , Carboplatino/administración & dosificación , Carboplatino/toxicidad , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Esquema de Medicación , Femenino , Humanos , Terapia de Inmunosupresión , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia , Paclitaxel/administración & dosificación , Paclitaxel/toxicidad , Gemcitabina

RESUMEN

33 women with advanced breast cancer resistant to anthracyclines were treated with paclitaxel 175 mg/m2 in a 3 h infusion every 3 weeks. The median age was 53 years (range 30-72) and the median performance status was 1 (range 0-2). 24 (73%) patients had visceral metastases while 22 (67%) had > or = two involved sites. 23 (70%) patients received anthracycline or mitoxantrone in an adjuvant setting and 21 (64%) for advanced disease. There were two (6%, 95% confidence interval (CI) 1-20%) complete responses (CRs) and 12 (36%, 95% CI 20-55%) partial responses (PRs). Median dose intensity of paclitaxel delivered was 58 mg/m2/week. Median time to progression was 24 weeks (range 4-61) and median survival was 41 weeks (range 8-66). Grade 3-4 toxicities included leucopenia (9%), stomatitis (3%), alopecia (91%), neurotoxicity (9%), infection (3%) and diarrhoea (3%). In conclusion, paclitaxel at a dose of 175 mg/m2 exhibits significant activity in advanced breast cancer resistant to anthracyclines.

Asunto(s)

Antineoplásicos Fitogénicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Paclitaxel/uso terapéutico , Adulto , Anciano , Antibióticos Antineoplásicos/uso terapéutico , Antineoplásicos Fitogénicos/efectos adversos , Neoplasias de la Mama/patología , Progresión de la Enfermedad , Resistencia a Antineoplásicos , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Paclitaxel/efectos adversos , Tasa de Supervivencia

Asunto(s)

Ampicilina/farmacología , Antibacterianos/farmacología , Cefuroxima/farmacología , Contracción Uterina/efectos de los fármacos , Animales , Dinoprost/farmacología , Femenino , Técnicas In Vitro , Ratas , Ratas Wistar

RESUMEN

The dopamine D4 receptor is of major interest in schizophrenia research due to its high affinity for the atypical neuroleptic clozapine and a high degree of variability in the receptor gene (DRD4). Although several genetic linkage analyses performed on schizophrenia multiplex families from different regions of the world have either excluded or failed to prove that DRD4 is a major genetic factor for the development of schizophrenia, analyses for moderate predisposing effects are still of significant interest. We performed a study examining differences in allele frequencies of 4 different DRD4 polymorphisms in schizophrenia patients and age, sex, and ethnic origin matched controls. None of these 4 polymorphisms showed evidence for genetic association with schizophrenia, although a trend towards excess of the allele with 7 repeats in the (48)n bp exon III polymorphism was observed. Complexities in the DRD4 genetic investigation and further analytic approaches are discussed.

Asunto(s)

Receptores de Dopamina D2/genética , Esquizofrenia/metabolismo , Femenino , Ligamiento Genético , Humanos , Masculino , Polimorfismo Genético , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D4 , Esquizofrenia/genética

Asunto(s)

Cartilla de ADN/genética , ADN Satélite/genética , Hibridación de Ácido Nucleico , Secuencia de Bases , Datos de Secuencia Molecular

RESUMEN

Current evidence suggests that interactions between the subchondral bone and the articular cartilage of mammalian diarthrodial joints may occur through the action of bone-associated peptide factors. However, there is no suitable organ culture model for studying these interactions. This study defines a long-term tissue culture system where the articular cartilage is coupled to the adjacent subchondral bone obtained from the proximal ends of bovine metacarpals. Autoradiography done over 3 mo., by utilizing [35S]SO4 incorporation into cartilage proteoglycan (PG) and a procedure for cutting non-decalcified bone, demonstrated similar numbers of silver grains over chondrocytes in all cartilage zones, including the bone-cartilage interface. Newly synthesized PG (NSPG) from the cartilage of the "coupled" system over a 3-wk period was primarily of large hydrodynamic size (Kav of 0.34). Comparable bovine articular and nasal cartilage slice systems, incubated for short periods of time, yielded similar and somewhat larger NSPG, respectively. Labeled chondroitin sulphate PG accumulating in the medium of primary chondrocyte monolayer cultures, derived from the cartilage of the coupled system at 0, 1, 2, and 3 wk, revealed two polydisperse subpopulations (Kav of 0.30 to 0.38 and 0.51 to 0.68). We conclude that this coupled bone-cartilage system is viable for prolonged periods, is suitable for studies on the metabolism of articular cartilage PGs, and seems to have some advantages over the cultured articular cartilage slice system.

Asunto(s)

Huesos/metabolismo , Cartílago Articular/metabolismo , Técnicas de Cultivo/métodos , Proteoglicanos/biosíntesis , Animales , Articulación del Tobillo , Autorradiografía , Huesos/anatomía & histología , Cartílago Articular/anatomía & histología , Bovinos , Estudios de Evaluación como Asunto , Factores de Tiempo

RESUMEN

Current evidence suggests that interactions between the subchondral bone and the articular cartilage of mammalian diarthrodial joints may occur through the action of bone-associated peptide factors. However, there is no suitable organ culture model for studying these interactions. This study defines a long-term tissue culture system where the articular cartilage is coupled to the adjacent subchondral bone obtained from the proximal ends of bovine metacarpals. Autoradiography done over 3 mo., by utilizing [(35)S]SO4 incorporation into cartilage proteoglycan (PG) and a procedure for cutting non-decalcified bone, demonstrated similar numbers of silver grains over chondrocytes in all cartilage zones, including the bone-cartilage interface. Newly synthesized PG (NSPG) from the cartilage of the "coupled" system over a 3-wk period was primarily of large hydrodynamic size (Kav of 0.34). Comparable bovine articular and nasal cartilage slice systems, incubated for short periods of time, yielded similar and somewhat larger NSPG, respectively. Labeled chondroitin sulphate PG accumulating in the medium of primary chondrocyte monolayer cultures, derived from the cartilage of the coupled system at 0, 1, 2, and 3 wk, revealed two polydisperse subpopulations (Kav of 0.30 to 0.38 and 0.51 to 0.68). We conclude that this coupled bone-cartilage system is viable for prolonged periods, is suitable for studies on the metabolism of articular cartilage PGs, and seems to have some advantages over the cultured articular cartilage slice system.