Drug repositioning explores the reuse of non-cancer drugs to treat tumors. In this work, we evalu... more Drug repositioning explores the reuse of non-cancer drugs to treat tumors. In this work, we evaluated the effect of the combination of chloroquine and propranolol on colorectal and triple-negative breast cancers. Using as in vitro models the colorectal cancer cell lines HCT116, HT29, and CT26, and as triple-negative breast cancer models the 4T1, M-406, and MDA-MB-231 cell lines, we evaluated the effect of the drugs combination on the viability, apoptosis, clonogenicity, and cellular migratory capacity. To explore the in vivo effects of the combination on tumor growth and metastasis development we employed graft models in BALB/c, nude, and CBi mice. In vitro studies showed that combined treatment decreased cell viability in a dose-dependent manner and increased apoptosis. Also, we demonstrated that these drugs act synergically and that it affects clonogenicity and migration. In vivo studies indicated that this drug combination was effective on colorectal models but only partially on ...
Drug repositioning refers to new uses for existing drugs outside the scope of the original medica... more Drug repositioning refers to new uses for existing drugs outside the scope of the original medical indications. This approach fastens the process of drug development allowing finding effective drugs with reduced side effects and lower costs. Colorectal cancer (CRC) is often diagnosed at advanced stages, when the probability of chemotherapy resistance is higher. Triple negative breast cancer (TNBC) is the most aggressive type of breast cancer, highly metastatic and difficult to treat. For both tumor types, available treatments are generally associated to severe side effects. In our work, we explored the effect of combining metformin and propranolol, two repositioned drugs, in both tumor types. We demonstrate that treatment affects viability, epithelial-mesenchymal transition and migratory potential of CRC cells as we described before for TNBC. We show that combined treatment affects different steps leading to metastasis in TNBC. Moreover, combined treatment is also effective preventi...
Experimental and clinical studies showed that the administration of cyclophosphamide (Cy) in low ... more Experimental and clinical studies showed that the administration of cyclophosphamide (Cy) in low doses leads to an enhancement of the antitumor immune response. Our objective was to study the modulation, if any, by low dose Cy, of T regulatory (Treg) and natural killer T (NKT) I cells, two cell populations of the innate immune response with opposing effects on the tumors, in a rat B cell lymphoma model. Inbred e rats were challenged s.c. with L-TACB lymphoma and on day 14 animals were distributed in two groups. Treated: injected i.p. with cyclophosphamide (10mg/kg of body weight) and injected i.p. with saline. Blood samples were taken from days 0 to 21 and the percentage of T regulatory and natural killer T I cells were determined by flow cytometry. We found that the increase of natural and inducible T regulatory cells of peripheral blood achieved during tumor growth was significantly downregulated by cyclophosphamide. On the contrary, natural killer T I cells were not modulated by ...
The introduction of the “maximum tolerated dose” in usual treatment protocols (and its concomitan... more The introduction of the “maximum tolerated dose” in usual treatment protocols (and its concomitant overt toxicity) made necessary the imposition of rest periods between cycles of therapy—a practice that not only involves re-growth of tumour cells, but also growth of selected clones resistant to the therapy. To avoid the problems caused by traditional chemotherapeutic regimens, a new modality of drug administration called “metronomic chemotherapy” has been proposed. This name makes reference to the chronic, equally spaced administration of (generally) low doses of various chemotherapeutic drugs without extended rest periods. The novelty of this treatment modality lies not only in its antitumour efficacy with very low toxicity, but also in a cell target switch, now aiming at tumour endothelial cells. The knowledge acquired in the experimental field of metronomic chemotherapy, plus the increasing experience that is being obtained in the clinical setting, will help to lead a change in t...
The aim of this paper was to identify the mechanism/s responsible of the antimetastatic effect of... more 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.
Increasing evidence suggests that immune responses are involved in the control of cancer and that... more Increasing evidence suggests that immune responses are involved in the control of cancer and that the immune system can be manipulated in different ways to recognize and attack tumors. Progress in immune-based strategies has opened new therapeutic avenues using a number of techniques destined to eliminate malignant cells. In the present review, we overview current knowledge on the importance, successes and difficulties of immunotherapy in liver tumors, including preclinical data available in animal models and information from clinical trials carried out during the lasts years. This review shows that new options for the treatment of advanced liver tumors are urgently needed and that there is a ground for future advances in the field.
Purpose: Interleukin-12 (IL-12) is an immunostimulatory cytokine with potent antitumor effects in... more Purpose: Interleukin-12 (IL-12) is an immunostimulatory cytokine with potent antitumor effects in several animal models. However, serious toxicity has been associated with its systemic application in humans. Gene transfer has emerged as a tool to specifically express therapeutic genes into the tumor/peritumoral milieu, thus avoiding systemic toxicity. The aim of this study was to analyze whether subtherapeutic doses of an adenovirus encoding IL-12 (AdIL-12) might synergize with low immunopotentiating doses of cyclophosphamide in the treatment of colorectal carcinoma. Experimental Design: The antitumor effect of combining a single low dose of cyclophosphamide with an intratumoral injection of AdIL-12 was evaluated in an in vivo murine colorectal carcinoma model. The immune responses achieved with different treatments were monitored, comparing the effect of combining both therapies with individual treatments. Results: The combined therapy induced a complete tumor regression in >50%...
Breast cancer is a heterogeneous disease with different known biological subclasses some of which... more Breast cancer is a heterogeneous disease with different known biological subclasses some of which are associated with immune cell infiltration. Studies in mice have shown that thymus-derived CD4+CD25+ regulatory T cells (Treg; FOXP3+ lymphocytes) inhibit the antitumor immune response. The presence of inflammatory cells may represent an immune response to the tumor, but could also potentially exhibit pro-tumor effects including stimulation of tumor invasion or angiogenesis. Angiogenesis has an important role in the progression of breast cancer. Microvessel density has been found to be strongly associated with features of tumor aggression as larger size and poor differentiation. It was observed that different characteristics of tumors like immune cells infiltration, number of Tregs and blood vessels density would be useful tools to anticipate the response to the therapy. The aim of this study was to analyze different cellular characteristics of primary tumors of patients with breast cancer and their relationship to the response to therapy. Samples of breast carcinomas (Stage I and II) (n=14) were analyzed. Foxp3 and CD34 expression was determined immunohistochemically on formalin-fixed, parafin-embedded tumor sections. Also, peritumor and intratumor lymphocytes infiltration was evaluated by hematoxylin-eosin staining. For quantification in 20 high magnification fields, a 0 (nule expression) to 6 (high expression) score was utilized. Confocal microcopy for Foxp3 was also used. Lymphocytes were mainly found in the intratumor (IT) area. Twelve over 14 patients (DF) that had a disease free survival of approximately 5 years showed an IT score for lymphocyte infiltration [median (range): 4 (2-6)] higher than that of 2/14 patients that relapsed (R) [2 (2-2)], p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3146. doi:10.1158/1538-7445.AM2011-3146
Metronomic chemotherapy refers to the chronic, equally spaced, delivery of low doses of different... more Metronomic chemotherapy refers to the chronic, equally spaced, delivery of low doses of different chemotherapeutic drugs, without extended interruptions. We have already demonstrated that the administration, as an intervention strategy, of metronomic CY plus DOX in M-406 mammary adenocarcinoma-bearing mice, inhibited tumor growth and metastases development, increasing the survival rate without toxicity. In order to know if that effect was unique to M-406 tumor or could be extended to other mammary carcinomas, our present aim was to study the effect of metronomic chemotherapy with CY + DOX in the M-234p tumor-model and the effect of the therapy in the level of circulating regulatory T cells (Tregs), considering the immunomodulatory effect of low doses of CY. Also, we intended to compare the therapeutic efficacy of the present schedule with that of MCT with CY + Celecoxib, previously done in the same tumor-model. CBi inbred female mice were s.c. challenged with M-234p cells (day 0). On day 10, mice were distributed in four experimental groups (n=6-8/group) that received: I) Control: 0.2ml of saline i.p. 3 times/week; II) CY (20mg/kg of body weight) daily, in the drinking water; III) Dox, i.p., 0,5mg/kg, of body weight, 3 times/week; IV) Treatment II + III. Tumors were measured and body weight was determined three times per week. Blood samples were taken at the beginning and at the end of the experiments to determine total leukocyte count and to evaluate by flow cytometry the percentage of Treg (CD4+ CD25+ Foxp3+) cells in serum. On day 31 a significant inhibition of tumor growth was evident in group III (mean ± SEM: 1166.4 ± 224.6 mm3) and IV (777.6 ± 170.6) with respect to control mice (3556.8 ± 895.3) (p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3511. doi:10.1158/1538-7445.AM2011-3511
Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Metronomic chemothe... more Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Metronomic chemotherapy (MCT), the chronic administration at regular intervals of low doses of chemotherapeutic drugs without extended rest periods, allows chronic treatment with therapeutic efficacy and low toxicity. Its molecular target is mainly the endothelial cell which is less prone to develop drug resistance. The aim of the present two-stage, phase I/II trial study was to determine the safety and efficacy of MCT with Cy plus Cel in metastatic breast cancer (MBC) patients progressing after standard chemotherapy and to identify early markers of therapeutic response. Patient inclusion criteria: 21-80 years old, more than 3 month of life expectancy, advanced breast cancer in progression after, at least, anthracyclines, taxanes and capecitabine treatments, at least one lesion according to RECIST criteria, ECOG scale β2, adequate bone marrow, hepatic, and renal function, normal calcemia, signed informed consent. Treatment: CY, 50 mg p.o./day + CEL, 200 mg p.o. bid. Study design: The trial has two stages with a final number of 25 patients, looking for a 25% general response rate (≥ error=0.10; ≤ error=0.05). Primary end point: clinical response, safety and tolerability. Toxicity: all the serious adverse events are registered by CTCAE criteria and followed until their resolution. Angiogenesis parameters: the serum level of vascular endothelial growth factor (VEGF) and thrombospondin 1 (TSP-1) were determined by ELISA, and the circulating endothelial cells (CECs) and circulating endothelial progenitor cells (CEPs) by flow cytometry. This protocol was authorized by the School of Medicine Bioethics Committee and by A.N.M.A.T. (National Regulatory Authority). During the first stage we have incorporated 13 patients. The time of permanence varied from 4 to 64 weeks (median=13). Presently, 4 patients are still in treatment. It was observed stable disease (SD) in 9/13 patients that lasted from 12 to 64 weeks (median=18) and partial response (PR) in 1/13. Treatment toxicity was very low: hematologic (2/13, grade I and II), gastric (4/13, grade I). There was no evidence of hepatic, renal or cardiac toxicities associated with the therapy. The performance status evaluated with the ECOG scale showed no modifications in 2/10 patients, a worse score in 3/10 and a better one in 5/10. The % of circulating CEPs showed a significant increase in non-responder patients (p=0.008) The serum VEGF concentration decreased as a function of time (p=0.004). Patients with the lowest VEGF/TSP-1 ratios showed the highest permanence. We conclude that the treatment showed a low toxicity profile, the therapeutic response consisted of SD during different periods of time, and one PR with no modifications or improvement of the performance status in a high proportion of patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1749. doi:1538-7445.AM2012-1749
Drug repositioning explores the reuse of non-cancer drugs to treat tumors. In this work, we evalu... more Drug repositioning explores the reuse of non-cancer drugs to treat tumors. In this work, we evaluated the effect of the combination of chloroquine and propranolol on colorectal and triple-negative breast cancers. Using as in vitro models the colorectal cancer cell lines HCT116, HT29, and CT26, and as triple-negative breast cancer models the 4T1, M-406, and MDA-MB-231 cell lines, we evaluated the effect of the drugs combination on the viability, apoptosis, clonogenicity, and cellular migratory capacity. To explore the in vivo effects of the combination on tumor growth and metastasis development we employed graft models in BALB/c, nude, and CBi mice. In vitro studies showed that combined treatment decreased cell viability in a dose-dependent manner and increased apoptosis. Also, we demonstrated that these drugs act synergically and that it affects clonogenicity and migration. In vivo studies indicated that this drug combination was effective on colorectal models but only partially on ...
Drug repositioning refers to new uses for existing drugs outside the scope of the original medica... more Drug repositioning refers to new uses for existing drugs outside the scope of the original medical indications. This approach fastens the process of drug development allowing finding effective drugs with reduced side effects and lower costs. Colorectal cancer (CRC) is often diagnosed at advanced stages, when the probability of chemotherapy resistance is higher. Triple negative breast cancer (TNBC) is the most aggressive type of breast cancer, highly metastatic and difficult to treat. For both tumor types, available treatments are generally associated to severe side effects. In our work, we explored the effect of combining metformin and propranolol, two repositioned drugs, in both tumor types. We demonstrate that treatment affects viability, epithelial-mesenchymal transition and migratory potential of CRC cells as we described before for TNBC. We show that combined treatment affects different steps leading to metastasis in TNBC. Moreover, combined treatment is also effective preventi...
Experimental and clinical studies showed that the administration of cyclophosphamide (Cy) in low ... more Experimental and clinical studies showed that the administration of cyclophosphamide (Cy) in low doses leads to an enhancement of the antitumor immune response. Our objective was to study the modulation, if any, by low dose Cy, of T regulatory (Treg) and natural killer T (NKT) I cells, two cell populations of the innate immune response with opposing effects on the tumors, in a rat B cell lymphoma model. Inbred e rats were challenged s.c. with L-TACB lymphoma and on day 14 animals were distributed in two groups. Treated: injected i.p. with cyclophosphamide (10mg/kg of body weight) and injected i.p. with saline. Blood samples were taken from days 0 to 21 and the percentage of T regulatory and natural killer T I cells were determined by flow cytometry. We found that the increase of natural and inducible T regulatory cells of peripheral blood achieved during tumor growth was significantly downregulated by cyclophosphamide. On the contrary, natural killer T I cells were not modulated by ...
The introduction of the “maximum tolerated dose” in usual treatment protocols (and its concomitan... more The introduction of the “maximum tolerated dose” in usual treatment protocols (and its concomitant overt toxicity) made necessary the imposition of rest periods between cycles of therapy—a practice that not only involves re-growth of tumour cells, but also growth of selected clones resistant to the therapy. To avoid the problems caused by traditional chemotherapeutic regimens, a new modality of drug administration called “metronomic chemotherapy” has been proposed. This name makes reference to the chronic, equally spaced administration of (generally) low doses of various chemotherapeutic drugs without extended rest periods. The novelty of this treatment modality lies not only in its antitumour efficacy with very low toxicity, but also in a cell target switch, now aiming at tumour endothelial cells. The knowledge acquired in the experimental field of metronomic chemotherapy, plus the increasing experience that is being obtained in the clinical setting, will help to lead a change in t...
The aim of this paper was to identify the mechanism/s responsible of the antimetastatic effect of... more 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.
Increasing evidence suggests that immune responses are involved in the control of cancer and that... more Increasing evidence suggests that immune responses are involved in the control of cancer and that the immune system can be manipulated in different ways to recognize and attack tumors. Progress in immune-based strategies has opened new therapeutic avenues using a number of techniques destined to eliminate malignant cells. In the present review, we overview current knowledge on the importance, successes and difficulties of immunotherapy in liver tumors, including preclinical data available in animal models and information from clinical trials carried out during the lasts years. This review shows that new options for the treatment of advanced liver tumors are urgently needed and that there is a ground for future advances in the field.
Purpose: Interleukin-12 (IL-12) is an immunostimulatory cytokine with potent antitumor effects in... more Purpose: Interleukin-12 (IL-12) is an immunostimulatory cytokine with potent antitumor effects in several animal models. However, serious toxicity has been associated with its systemic application in humans. Gene transfer has emerged as a tool to specifically express therapeutic genes into the tumor/peritumoral milieu, thus avoiding systemic toxicity. The aim of this study was to analyze whether subtherapeutic doses of an adenovirus encoding IL-12 (AdIL-12) might synergize with low immunopotentiating doses of cyclophosphamide in the treatment of colorectal carcinoma. Experimental Design: The antitumor effect of combining a single low dose of cyclophosphamide with an intratumoral injection of AdIL-12 was evaluated in an in vivo murine colorectal carcinoma model. The immune responses achieved with different treatments were monitored, comparing the effect of combining both therapies with individual treatments. Results: The combined therapy induced a complete tumor regression in >50%...
Breast cancer is a heterogeneous disease with different known biological subclasses some of which... more Breast cancer is a heterogeneous disease with different known biological subclasses some of which are associated with immune cell infiltration. Studies in mice have shown that thymus-derived CD4+CD25+ regulatory T cells (Treg; FOXP3+ lymphocytes) inhibit the antitumor immune response. The presence of inflammatory cells may represent an immune response to the tumor, but could also potentially exhibit pro-tumor effects including stimulation of tumor invasion or angiogenesis. Angiogenesis has an important role in the progression of breast cancer. Microvessel density has been found to be strongly associated with features of tumor aggression as larger size and poor differentiation. It was observed that different characteristics of tumors like immune cells infiltration, number of Tregs and blood vessels density would be useful tools to anticipate the response to the therapy. The aim of this study was to analyze different cellular characteristics of primary tumors of patients with breast cancer and their relationship to the response to therapy. Samples of breast carcinomas (Stage I and II) (n=14) were analyzed. Foxp3 and CD34 expression was determined immunohistochemically on formalin-fixed, parafin-embedded tumor sections. Also, peritumor and intratumor lymphocytes infiltration was evaluated by hematoxylin-eosin staining. For quantification in 20 high magnification fields, a 0 (nule expression) to 6 (high expression) score was utilized. Confocal microcopy for Foxp3 was also used. Lymphocytes were mainly found in the intratumor (IT) area. Twelve over 14 patients (DF) that had a disease free survival of approximately 5 years showed an IT score for lymphocyte infiltration [median (range): 4 (2-6)] higher than that of 2/14 patients that relapsed (R) [2 (2-2)], p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3146. doi:10.1158/1538-7445.AM2011-3146
Metronomic chemotherapy refers to the chronic, equally spaced, delivery of low doses of different... more Metronomic chemotherapy refers to the chronic, equally spaced, delivery of low doses of different chemotherapeutic drugs, without extended interruptions. We have already demonstrated that the administration, as an intervention strategy, of metronomic CY plus DOX in M-406 mammary adenocarcinoma-bearing mice, inhibited tumor growth and metastases development, increasing the survival rate without toxicity. In order to know if that effect was unique to M-406 tumor or could be extended to other mammary carcinomas, our present aim was to study the effect of metronomic chemotherapy with CY + DOX in the M-234p tumor-model and the effect of the therapy in the level of circulating regulatory T cells (Tregs), considering the immunomodulatory effect of low doses of CY. Also, we intended to compare the therapeutic efficacy of the present schedule with that of MCT with CY + Celecoxib, previously done in the same tumor-model. CBi inbred female mice were s.c. challenged with M-234p cells (day 0). On day 10, mice were distributed in four experimental groups (n=6-8/group) that received: I) Control: 0.2ml of saline i.p. 3 times/week; II) CY (20mg/kg of body weight) daily, in the drinking water; III) Dox, i.p., 0,5mg/kg, of body weight, 3 times/week; IV) Treatment II + III. Tumors were measured and body weight was determined three times per week. Blood samples were taken at the beginning and at the end of the experiments to determine total leukocyte count and to evaluate by flow cytometry the percentage of Treg (CD4+ CD25+ Foxp3+) cells in serum. On day 31 a significant inhibition of tumor growth was evident in group III (mean ± SEM: 1166.4 ± 224.6 mm3) and IV (777.6 ± 170.6) with respect to control mice (3556.8 ± 895.3) (p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3511. doi:10.1158/1538-7445.AM2011-3511
Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Metronomic chemothe... more Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Metronomic chemotherapy (MCT), the chronic administration at regular intervals of low doses of chemotherapeutic drugs without extended rest periods, allows chronic treatment with therapeutic efficacy and low toxicity. Its molecular target is mainly the endothelial cell which is less prone to develop drug resistance. The aim of the present two-stage, phase I/II trial study was to determine the safety and efficacy of MCT with Cy plus Cel in metastatic breast cancer (MBC) patients progressing after standard chemotherapy and to identify early markers of therapeutic response. Patient inclusion criteria: 21-80 years old, more than 3 month of life expectancy, advanced breast cancer in progression after, at least, anthracyclines, taxanes and capecitabine treatments, at least one lesion according to RECIST criteria, ECOG scale β2, adequate bone marrow, hepatic, and renal function, normal calcemia, signed informed consent. Treatment: CY, 50 mg p.o./day + CEL, 200 mg p.o. bid. Study design: The trial has two stages with a final number of 25 patients, looking for a 25% general response rate (≥ error=0.10; ≤ error=0.05). Primary end point: clinical response, safety and tolerability. Toxicity: all the serious adverse events are registered by CTCAE criteria and followed until their resolution. Angiogenesis parameters: the serum level of vascular endothelial growth factor (VEGF) and thrombospondin 1 (TSP-1) were determined by ELISA, and the circulating endothelial cells (CECs) and circulating endothelial progenitor cells (CEPs) by flow cytometry. This protocol was authorized by the School of Medicine Bioethics Committee and by A.N.M.A.T. (National Regulatory Authority). During the first stage we have incorporated 13 patients. The time of permanence varied from 4 to 64 weeks (median=13). Presently, 4 patients are still in treatment. It was observed stable disease (SD) in 9/13 patients that lasted from 12 to 64 weeks (median=18) and partial response (PR) in 1/13. Treatment toxicity was very low: hematologic (2/13, grade I and II), gastric (4/13, grade I). There was no evidence of hepatic, renal or cardiac toxicities associated with the therapy. The performance status evaluated with the ECOG scale showed no modifications in 2/10 patients, a worse score in 3/10 and a better one in 5/10. The % of circulating CEPs showed a significant increase in non-responder patients (p=0.008) The serum VEGF concentration decreased as a function of time (p=0.004). Patients with the lowest VEGF/TSP-1 ratios showed the highest permanence. We conclude that the treatment showed a low toxicity profile, the therapeutic response consisted of SD during different periods of time, and one PR with no modifications or improvement of the performance status in a high proportion of patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1749. doi:1538-7445.AM2012-1749
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