19 abril 2011
Trabectedin: Safety and Efficacy in the Treatment of Advanced Sarcoma .
Authors: Csaba Gajdos and Anthony Elias . Department of Surgery, GITES Division.Journal: Clinical Medicine Insights: Oncology .
Abstract
Soft tissue sarcomas (STS) are a rare group of malignancies with multiple different subtypes. Close to half of intermediate or high grade STS develop metastatic disease. Treatment of recurrent/metastatic sarcomas is quite challenging with only a few drugs showing measurable benefits. Trabectedin (ecteinascidin 743, ET-743, Yondelis) is a newly developed alkylating agent that has shown significant broad spectrum potential as a single agent second line drug alone or in combination particularly in the treatment of liposarcomas and leiomyosarcomas. Clinical benefit rates seem to favor its use especially in pretreated patients with recurrent/metastatic disease. The drug is well tolerated in general but hepatotoxicity and hematologic side effects are common. Approved in Europe, the currently ongoing Phase III trials along with the already existing clinical evidence may provide enough data for the Food and Drug Administration for an approval in the US.
18 abril 2011
15 abril 2011
TeloVac . Prueban en humanos vacuna contra el cáncer de páncreas .
Más de medio centenar de hospitales del Reino Unido comenzaron la fase de pruebas en seres humanos de una vacuna para el cáncer de páncreas, el que presenta la menor tasa de supervivencia.
Más de mil pacientes con la enfermedad en estado avanzado se han incorporado el proyecto de pruebas de la TeloVac.
Aunque las vacunas normalmente se asocian a la prevención de infecciones, en el caso de la TeloVac, busca una estrategia diferente: estimular el sistema inmunológico para que se enfrente a las células cancerígenas.
...
Más de mil pacientes con la enfermedad en estado avanzado se han incorporado el proyecto de pruebas de la TeloVac.
Aunque las vacunas normalmente se asocian a la prevención de infecciones, en el caso de la TeloVac, busca una estrategia diferente: estimular el sistema inmunológico para que se enfrente a las células cancerígenas.
...
14 abril 2011
Inicio Fase II estudio Yondelis para cáncer de mama (valoraciones) .
Los analistas de Ahorro Corporación valoran la noticia como positiva para Zeltia, por el avance en los estudios que esto implica. En cualquier caso, no hay que olvidar que se trata de un estudio de fase II.
Recomendación comprar con un precio objetivo 4,50 euros.
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Los analistas de La Caixa valoran esta noticia como positiva pero que no debería tener impacto sobre la cotización, por encontrarse aún en una fase temprana del estudio clínico.
Recomendación comprar con un precio objetivo de 4,3 euros por acción.
Recomendación comprar con un precio objetivo 4,50 euros.
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Los analistas de La Caixa valoran esta noticia como positiva pero que no debería tener impacto sobre la cotización, por encontrarse aún en una fase temprana del estudio clínico.
Recomendación comprar con un precio objetivo de 4,3 euros por acción.
El uso regular de analgésicos, como la aspirina o el ibuprofeno, reduciría las probabilidades individuales de desarrollar cánceres de colon , ...
... a veces hasta un 50 por ciento, según expertos del Instituto Nacional del Cáncer en Estados Unidos.
La investigación demuestra también que el beneficio se extiende a las personas con antecedentes familiares de la enfermedad, y que tienen más riesgo de desarrollarla.
Sin embargo tenga en cuenta que el consumo de estos medicamentos “eleva el riesgo de desarrollar úlceras y hemorragias gastrointestinales”, indican los especialistas norteamericanos.
La investigación demuestra también que el beneficio se extiende a las personas con antecedentes familiares de la enfermedad, y que tienen más riesgo de desarrollarla.
Sin embargo tenga en cuenta que el consumo de estos medicamentos “eleva el riesgo de desarrollar úlceras y hemorragias gastrointestinales”, indican los especialistas norteamericanos.
Descubren molécula natural que protege contra el cáncer de mama .
La proteina IL25 que es capaz de destruir las celulas cancerosas sin dañar las sanas. Se trata de un mecanismo innato de defensa contra la metástasis en el tejido mamario
...
...
13 abril 2011
PharmaMar ha iniciado una Fase II con Yondelis® en Cáncer de Mama Avanzado y que han recibido al menos dos líneas previas de tratamiento.
http://www.zeltia.es/media/docs/uthjxkhw.pdf?ie=UTF-8&oe=UTF-8&q=prettyphoto&iframe=true&width=100%&height=100%
Las pacientes se dividirán en dos grupos según los niveles de una proteína llamada XPG que está presente en los tumores y que se ha relacionado con el mecanismo de acción de este medicamento. En un estudio previo, también en cáncer de mama, las pacientes que presentaban niveles altos de la proteína XPG mostraron una mejor respuesta al tratamiento con 'Yondelis'.
El estudio incluirá inicialmente un total de 40 pacientes, pudiendo llegar hasta cien, dependiendo de la actividad que se observe en cada uno de los grupos. La evaluación de la actividad se basará en el porcentaje de pacientes en las que la enfermedad no haya progresado en los primeros cuatro meses posteriores al comienzo del tratamiento.
Las pacientes se dividirán en dos grupos según los niveles de una proteína llamada XPG que está presente en los tumores y que se ha relacionado con el mecanismo de acción de este medicamento. En un estudio previo, también en cáncer de mama, las pacientes que presentaban niveles altos de la proteína XPG mostraron una mejor respuesta al tratamiento con 'Yondelis'.El estudio incluirá inicialmente un total de 40 pacientes, pudiendo llegar hasta cien, dependiendo de la actividad que se observe en cada uno de los grupos. La evaluación de la actividad se basará en el porcentaje de pacientes en las que la enfermedad no haya progresado en los primeros cuatro meses posteriores al comienzo del tratamiento.
12 abril 2011
Namendia ( Forest Laboratories Inc y Merz Pharma ) para Alzheimer leve obtuvo 1200 Mill $$ en ventas en EEUU en 2010 ... y es Ineficaz
... Actualmente no existen fármacos que puedan evitar el avance de la enfermedad . Por lo que se esta a la espera de que aparezca el Primer Farmaco a nivel mundial que sea eficaz frente al Alzheimer ...
11 abril 2011
La causa de los niños robados sentará a «miles» de responsables en el banquillo .
... La empresa que gestiona el banco de ADN de los afectados (Genómica SAU) ha comprobado ya una "primera coincidencia" entre dos mujeres, una sería la madre y otra la hija, adoptada "ilegalmente", aunque con apariencia legal, en 1971 en Barcelona.
"Hemos obtenido el primer resultado positivo del reencuentro de una madre y ver una madre abrazar a su hija no tiene precio, por lo que esperamos que sea el primero de muchos reencuentros. A esta madre le dijeron que su hija había muerto y a la hija la dieron en adopción bajo apariencia de legalidad", ha apostillado.
...
La responsable de esos cruces de perfiles genéticos en la base de datos, Amaya Gorostiza, del Centro Genética Genómica S.A.U., avala las expectativas de este proceso, y adelanta que la semana que viene van a trasladarse a Sevilla para la toma de muestras en una región, Andalucía, que encabeza el número de afectados denunciantes, seguida de Madrid y Cataluña. «El banco crece de manera muy rápida, y por eso, confiamos en que dé más frutos próximamente», asevera Gorostiza.
...
"Hemos obtenido el primer resultado positivo del reencuentro de una madre y ver una madre abrazar a su hija no tiene precio, por lo que esperamos que sea el primero de muchos reencuentros. A esta madre le dijeron que su hija había muerto y a la hija la dieron en adopción bajo apariencia de legalidad", ha apostillado.
...
La responsable de esos cruces de perfiles genéticos en la base de datos, Amaya Gorostiza, del Centro Genética Genómica S.A.U., avala las expectativas de este proceso, y adelanta que la semana que viene van a trasladarse a Sevilla para la toma de muestras en una región, Andalucía, que encabeza el número de afectados denunciantes, seguida de Madrid y Cataluña. «El banco crece de manera muy rápida, y por eso, confiamos en que dé más frutos próximamente», asevera Gorostiza.
...
10 abril 2011
Josep Baselga : «Si hay que cerrar centros de investigación, hagámoslo» .
Pertenece a la élite mundial de la investigación del cáncer. Su lucha está en el laboratorio y a pie de cama del enfermo «para no perder el contacto con la realidad». Acaba de recibir el premio ABC Salud al «Médico del año»
...
...
09 abril 2011
Area woman struggles with two kinds of cancer .
... Leiomyosarcoma is an aggressive small cell muscle tissue cancer only found in women that usually starts in the area of the uterus.
“My doctor said it was treatable, but not curable,” Lader said, “which means I will have periods of remission and recurrence.”
She tried four kinds of chemotherapy, but none worked. Through the connections of her oncologist at McCullough Hyde Memorial Hospital in Oxford, she entered into a trial for Yondelis, an anti-tumor drug that has been used in Europe and Russia for over 25 years but hasn’t met FDA approval in the U.S. One good thing about the treatments is that they have no side effects, she said.
Every three weeks, she drives to Louisville, Ky., for treatments on Friday, then comes back to work on Monday morning.
And, she said, being able to live a normal life has been crucial to keeping an optimistic outlook.
“I’ve been extremely blessed,” she said. “That’s all I can say.”
“My doctor said it was treatable, but not curable,” Lader said, “which means I will have periods of remission and recurrence.”
She tried four kinds of chemotherapy, but none worked. Through the connections of her oncologist at McCullough Hyde Memorial Hospital in Oxford, she entered into a trial for Yondelis, an anti-tumor drug that has been used in Europe and Russia for over 25 years but hasn’t met FDA approval in the U.S. One good thing about the treatments is that they have no side effects, she said.
Every three weeks, she drives to Louisville, Ky., for treatments on Friday, then comes back to work on Monday morning.
And, she said, being able to live a normal life has been crucial to keeping an optimistic outlook.
“I’ve been extremely blessed,” she said. “That’s all I can say.”
El abuso del alcohol es responsable directo de 15.600 tumores al año .
La bebida está ligada con hasta siete tipos de cáncer - El consumo máximo recomendado son dos copas de vino al día en hombres, la mitad en mujeres .
...
...
07 abril 2011
Pharma Mar realiza Tres presentaciones en el Congreso de la AACR de Dos de sus Farmacos de Nueva Generación : Irvalec y PM1183 .
De la vieja generacion tan solo quedan Yondelis y Aplidin .
Zalypsis , Irvalec , PM1183 y PM060184 son los Farmacos de Nueva generacion de Pharma Mar , algunos de ellos son Analogos de Viejos conocidos por lo que les imprime mayor potencial ... un antes y un despues en la I+D .
*************************************************
MADRID, 7 Abr. (EUROPA PRESS) -
PharmaMar, compañía biofarmacéutica del Grupo Zeltia, ha presentado los resultados obtenidos con los antitumorales de origen marino 'Irvalec' y 'PM01183', en los que se ha confirmado el efecto del primero sobre la membrana plasmática y la actividad del segundo sobre las células resistentes al platino y su capacidad de disminuir la actividad del sistema NER (Nucleotide Excision Repair, por sus siglas en inglés).
Las conclusiones, expuestas durante la Reunión Anual de la American Association for Cancer Research (AACR), que se acaba de celebrar en Orlando (Florida), de 'PM01183' muestran las propiedades combinatorias favorables con la mayoría de los compuestos con los que se han realizado los ensayos, "habiendo fuertes sinergias con irinotecan, paclitaxel y dacarbazine".
**************************************************
Conclusiones de las Tres Presentaciones :
PM1183 :
Purpose: PM01183 is a novel marine-derived covalent DNA binder with structural similarity to trabectedin, but with different pharmacokinetics as indicated by early clinical studies. Resistance to DNA alkylators, and platinum regimens in particular, is often accompanied by increased nucleotide excision repair (NER) activity. We here characterize the repair of PM01183 and trabectedin and determine the activity of the two agents toward cells with acquired platinum resistance.
Experimental Design: The activity of PM01183 and trabectedin toward platinum-resistant ovarian or colon cancer cells was determined by the MTT viability assay. NER activities were determined by unscheduled DNA synthesis (DNA repair synthesis) and adduct removal using adduct-specific antibodies. The activity of PM01183 and cisplatin combinations was evaluated by Chou and Talalay analysis.
Results: All cisplatin- or oxaliplatin-resistant cell lines showed unchanged or enhanced sensitivity to PM01183 and trabectedin, whatever their NER levels. Neither compound was repaired by NER, but both were able to interfere with the NER process thereby attenuating the repair of bona fide NER substrates. Accordingly, combinations of PM01183 and cisplatin were at least additive toward both parental and cisplatin-resistant ovarian cancer cells.
Conclusions: We here show that PM01183 has activity toward cells with acquired platinum resistance. PM01183 is not repaired by NER, but is able to attenuate the NER process. Accordingly, combinations of PM01183 and cisplatin are at least additive toward both parental and cisplatin-resistant carcinoma cells. These data provide a mechanistic basis to support clinical trials of PM01183 in combination with cisplatin toward both platinum-sensitive and -resistant tumors.
*************************
PM1183 :
PM01183 is a new synthetic tetrahydroisoquinoline alkaloid that binds to selected DNA sequences and promotes apoptosis by inducing double-strand breaks at nanomolar concentrations. PM01183 displays significant antitumor activity in several murine models of human cancer. PM01183 is currently in phase I/II clinical development for cancer treatment. Nonclinical combination studies are increasingly relevant during the development of any anticancer compound. As such, PM01183 was assayed in combination (two-drugs) with representatives of alkylating agents (dacarbazine, temozolomide and cisplatin), antimetabolites (5-FU and gemcitabine), DNA-topoisomerase inhibitors (irinotecan and doxorubicin) and tubulin binding agents (paclitaxel and vinorelbine). Different models were used depending on the combination explored: STS (HT1080) for dacarbazine; glioma (U-87 MG) for temozolomide; gastric (HGC-27) for cisplatin and 5-FU; pancreas (SW1990) for gemcitabine; colon (HT-29) and NSCLC (H460) for irinotecan; and ovarian (A2780) for doxorubicin, paclitaxel and vinorelbine. Athymic nu/nu mice bearing tumors (ca. 150 mm3) were randomly allocated to 13 treatment groups: i) placebo; ii) PM01183 at 4 different dose levels, namely MTD (0.180 mg/kg), 0.75MTD, 0.5MTD and 0.25MTD; iii) Compound to be combined, at 4 different dose levels MTD, 0.75MTD, 0.5MTD and 0.25MTD; and, iv) PM01183 plus the combined compound, administered with the combination at (1+1), (0.75+0.75), (0.50+0.50) and (0.25+0.25) of MTD ratios. The antitumor activity was followed by T/C, (change in tumor volume for each treated -T- and placebo -C- groups during placebo-treated survival period). Then, the fraction affected (Fa) by the treatment was calculated (1-T/C) and, the combination index (CI) by the CI-isobol method determined. Synergism (CI ≤ 1 at Fa > 0.8) was recorded when PM01183 was combined with dacarbazine (HT1080), cisplatin (HGC-27), 5-fluororacil (HGC-27), gemcitabine (SW1990), irinotecan (H460), doxorubicin (A2780), paclitaxel (A2780) and vinorelbine (A2780).
****************************
Irvalec :
Irvalec® (PM02734, elisidepsin) is a marine-derived cytotoxic depsipeptide currently undergoing phase II clinical studies. Irvalec® inserts and self-organize in the plasma membrane of tumor cells, rapidly inducing loss of membrane integrity, cell permeabilization, an increase in membrane ion conductance and calcium movement across the membrane, resulting in a very rapid necrotic cell death.
By continuous exposure of lung A549 and colon HCT-116 human tumor cells to stepwise, increasing concentratrions of Irvalec®, we established two resistant subclones of these cell lines, A549-Irv and HCT-116-Irv. In dose-response cytotoxicity assays, A549-Irv and HCT-116-Irv cells showed GI50 values of 32 and >50 μM, respectively, representing resistance indexes of 8.5 and >10.8 as compared to their wt counterparts.
Resistant cells did not show any of the morphological and physiological responses to Irvalec® observed in wt cells. No significant cross-resistance to other standard antitumor compounds was detected. Interestingly, A549-Irv but not HCT-116-Irv cells, were more sensitive to tubulin interacting agents, including taxanes and vinca alkaloids, than the wt cells, suggesting a role for the cytoskeleton in the mechanism of the acquired resistance to Irvalec®. Analysis of protein expression in wt and resistant cells showed a significant decrease of certain membrane or membrane-associated proteins in resistant cells; cytosolic proteins were virtually unaffected. Among the proteins whose expression was significantly decreased in resistant cells, E-cadherin was the most outstanding, being its expression nearly abolished in A549-Irv resistant cells. These results indicate that changes in the cell membrane composition of the resistant cells occurred during the process of establishment, that may involve trafficking of proteins from the golgi to the membrane or protein insertion and/or stability in the lipid bilayer.
Zalypsis , Irvalec , PM1183 y PM060184 son los Farmacos de Nueva generacion de Pharma Mar , algunos de ellos son Analogos de Viejos conocidos por lo que les imprime mayor potencial ... un antes y un despues en la I+D .
*************************************************
MADRID, 7 Abr. (EUROPA PRESS) -
PharmaMar, compañía biofarmacéutica del Grupo Zeltia, ha presentado los resultados obtenidos con los antitumorales de origen marino 'Irvalec' y 'PM01183', en los que se ha confirmado el efecto del primero sobre la membrana plasmática y la actividad del segundo sobre las células resistentes al platino y su capacidad de disminuir la actividad del sistema NER (Nucleotide Excision Repair, por sus siglas en inglés).
Las conclusiones, expuestas durante la Reunión Anual de la American Association for Cancer Research (AACR), que se acaba de celebrar en Orlando (Florida), de 'PM01183' muestran las propiedades combinatorias favorables con la mayoría de los compuestos con los que se han realizado los ensayos, "habiendo fuertes sinergias con irinotecan, paclitaxel y dacarbazine".
**************************************************
Conclusiones de las Tres Presentaciones :
PM1183 :
Purpose: PM01183 is a novel marine-derived covalent DNA binder with structural similarity to trabectedin, but with different pharmacokinetics as indicated by early clinical studies. Resistance to DNA alkylators, and platinum regimens in particular, is often accompanied by increased nucleotide excision repair (NER) activity. We here characterize the repair of PM01183 and trabectedin and determine the activity of the two agents toward cells with acquired platinum resistance.
Experimental Design: The activity of PM01183 and trabectedin toward platinum-resistant ovarian or colon cancer cells was determined by the MTT viability assay. NER activities were determined by unscheduled DNA synthesis (DNA repair synthesis) and adduct removal using adduct-specific antibodies. The activity of PM01183 and cisplatin combinations was evaluated by Chou and Talalay analysis.
Results: All cisplatin- or oxaliplatin-resistant cell lines showed unchanged or enhanced sensitivity to PM01183 and trabectedin, whatever their NER levels. Neither compound was repaired by NER, but both were able to interfere with the NER process thereby attenuating the repair of bona fide NER substrates. Accordingly, combinations of PM01183 and cisplatin were at least additive toward both parental and cisplatin-resistant ovarian cancer cells.
Conclusions: We here show that PM01183 has activity toward cells with acquired platinum resistance. PM01183 is not repaired by NER, but is able to attenuate the NER process. Accordingly, combinations of PM01183 and cisplatin are at least additive toward both parental and cisplatin-resistant carcinoma cells. These data provide a mechanistic basis to support clinical trials of PM01183 in combination with cisplatin toward both platinum-sensitive and -resistant tumors.
*************************
PM1183 :
PM01183 is a new synthetic tetrahydroisoquinoline alkaloid that binds to selected DNA sequences and promotes apoptosis by inducing double-strand breaks at nanomolar concentrations. PM01183 displays significant antitumor activity in several murine models of human cancer. PM01183 is currently in phase I/II clinical development for cancer treatment. Nonclinical combination studies are increasingly relevant during the development of any anticancer compound. As such, PM01183 was assayed in combination (two-drugs) with representatives of alkylating agents (dacarbazine, temozolomide and cisplatin), antimetabolites (5-FU and gemcitabine), DNA-topoisomerase inhibitors (irinotecan and doxorubicin) and tubulin binding agents (paclitaxel and vinorelbine). Different models were used depending on the combination explored: STS (HT1080) for dacarbazine; glioma (U-87 MG) for temozolomide; gastric (HGC-27) for cisplatin and 5-FU; pancreas (SW1990) for gemcitabine; colon (HT-29) and NSCLC (H460) for irinotecan; and ovarian (A2780) for doxorubicin, paclitaxel and vinorelbine. Athymic nu/nu mice bearing tumors (ca. 150 mm3) were randomly allocated to 13 treatment groups: i) placebo; ii) PM01183 at 4 different dose levels, namely MTD (0.180 mg/kg), 0.75MTD, 0.5MTD and 0.25MTD; iii) Compound to be combined, at 4 different dose levels MTD, 0.75MTD, 0.5MTD and 0.25MTD; and, iv) PM01183 plus the combined compound, administered with the combination at (1+1), (0.75+0.75), (0.50+0.50) and (0.25+0.25) of MTD ratios. The antitumor activity was followed by T/C, (change in tumor volume for each treated -T- and placebo -C- groups during placebo-treated survival period). Then, the fraction affected (Fa) by the treatment was calculated (1-T/C) and, the combination index (CI) by the CI-isobol method determined. Synergism (CI ≤ 1 at Fa > 0.8) was recorded when PM01183 was combined with dacarbazine (HT1080), cisplatin (HGC-27), 5-fluororacil (HGC-27), gemcitabine (SW1990), irinotecan (H460), doxorubicin (A2780), paclitaxel (A2780) and vinorelbine (A2780).
****************************
Irvalec :
Irvalec® (PM02734, elisidepsin) is a marine-derived cytotoxic depsipeptide currently undergoing phase II clinical studies. Irvalec® inserts and self-organize in the plasma membrane of tumor cells, rapidly inducing loss of membrane integrity, cell permeabilization, an increase in membrane ion conductance and calcium movement across the membrane, resulting in a very rapid necrotic cell death.
By continuous exposure of lung A549 and colon HCT-116 human tumor cells to stepwise, increasing concentratrions of Irvalec®, we established two resistant subclones of these cell lines, A549-Irv and HCT-116-Irv. In dose-response cytotoxicity assays, A549-Irv and HCT-116-Irv cells showed GI50 values of 32 and >50 μM, respectively, representing resistance indexes of 8.5 and >10.8 as compared to their wt counterparts.
Resistant cells did not show any of the morphological and physiological responses to Irvalec® observed in wt cells. No significant cross-resistance to other standard antitumor compounds was detected. Interestingly, A549-Irv but not HCT-116-Irv cells, were more sensitive to tubulin interacting agents, including taxanes and vinca alkaloids, than the wt cells, suggesting a role for the cytoskeleton in the mechanism of the acquired resistance to Irvalec®. Analysis of protein expression in wt and resistant cells showed a significant decrease of certain membrane or membrane-associated proteins in resistant cells; cytosolic proteins were virtually unaffected. Among the proteins whose expression was significantly decreased in resistant cells, E-cadherin was the most outstanding, being its expression nearly abolished in A549-Irv resistant cells. These results indicate that changes in the cell membrane composition of the resistant cells occurred during the process of establishment, that may involve trafficking of proteins from the golgi to the membrane or protein insertion and/or stability in the lipid bilayer.
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