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M Barajas

Publications and source records attributed to M Barajas.

15 recordsLinked to original sources
PubMed2006

Increased VEGF levels induced by anti-VEGF treatment are independent of tumor burden in colorectal carcinomas in mice.

Inhibition of vascular endothelial growth factor (VEGF) by gene transfer techniques was effectively applied to control experimental tumor growth, whereas effects on systemic VEGF levels had not been investigated. Therefore, we evaluated the effect of VEGF inhibition by adenoviral-mediated gene delivery of a dominant-negative soluble fragment of FLK-1 (sFlk-1) on systemic VEGF levels, organ-specific VEGF-RNA expression and antitumor efficacy in a murine colorectal cancer (CRC) tumor model. Vector function of AdsFlk-1 was shown by Western blot analysis and transgene expression was documented over a time period of 42 days in the serum of treated mice. Although cell supernatant of CT26 cells contained considerable levels of VEGF, systemic VEGF levels in the serum of tumor-bearing mice remained unaffected. Interestingly, mice that were systemically treated with AdsFlk-1 showed a strong upraise of circulating VEGF, whereas VEGF remained at background levels in the control. Vascular endothelial growth factor was increased not only in tumor bearing but also in healthy, tumor-free mice. Vascular endothelial growth factor determination in liver tissue homogenates showed a 16.5-fold upraise in AdsFlk-1-treated animals as compared to the AdLacZ control. Consecutively, systemic small interfering RNA injection targeted against VEGF reverted elevated VEGF levels almost back to normal levels. In spite of elevated VEGF levels, AdsFlk-1 administration showed significant antitumor effects in a subcutaneous metastatic CRC tumor model. There was no significant correlation between antitumour treatment response and VEGF levels in this model. Collectively, we conclude that the systemic administration of AdsFlk-1 had significant inhibitory effects on metastatic CRC tumor growth in spite of elevated systemic VEGF levels and that VEGF serum concentrations did not correlate to tumor burden and antitumor treatment response in this model.

Adenoviridae↗
PubMed2004

Treatment of colorectal and hepatocellular carcinomas by adenoviral mediated gene transfer of endostatin and angiostatin-like molecule in mice.

AIM AND METHOD: In this study, we explored the responsiveness of different tumour entities (colorectal carcinoma (CRC), hepatocellular carcinoma (HCC), and the murine Lewis lung carcinoma (LLC)) to angiostatic antitumour treatment with two recombinant adenoviral vectors encoding angiostatin-like molecule (AdK1-3) and endostatin (Adendo). RESULTS: AdK1-3 and Adendo exerted inhibitory biological functions on endothelial cell proliferation, migration, and tube formation in vitro. AdK1-3 inhibited significantly endothelial cell infiltration in vascular endothelial growth factor embedded Matrigel plugs in mice whereas Adendo showed only minor effects. Both AdK1-3 and Adendo induced similar antitumour effects in the LLC tumour model in immune competent C57BL/6 mice but AdK1-3 had stronger inhibitory effects in athymic mice. Furthermore, AdK1-3 inhibited tumour growth in a murine CRC and human HCC model but was ineffective in a human CRC model. In contrast, Adendo did not reduce tumour progress in either of these tumour models although AdK1-3 and Adendo effectively reduced intratumoral microvessel density in LLC tumours. CONCLUSION: Our data demonstrate that angiostatic gene therapy may form a feasible strategy for the treatment of established hepatocellular carcinomas and that in vivo antitumour efficacy of angiostatic proteins is tumour specific.

Adenoviridae↗
PubMed2003

Pancreatic cancer escape variants that evade immunogene therapy through loss of sensitivity to IFNgamma-induced apoptosis.

Combined injections into experimental tumor nodules of adenovirus encoding IL-12 and certain chemokines are capable to induce immune-mediated complete regressions. In this study, we found that the combination of two adenoviruses, one encoding IL-12 and other MIP3alpha (AdCMVIL-12+AdCMVMIP3alpha) was very successful in treating CT-26-derived colon carcinomas. However, in experimental tumors generated from the pancreatic carcinoma cell line Panc02 such combined treatment induces 50% of macroscopic complete regressions, although local relapses within 1 week are almost constant. We derived cell lines from such relapsing tumors and found that experimental malignancies derived from their inoculum were not amenable to treatment in any case with AdCMVIL-12+AdCMVMIP-3alpha. Importantly, relapsing cell lines were insensitive to in vitro induction of apoptosis by IFNgamma, in clear contrast with the original Panc02 cells. Comparative analyses by cDNA arrays of relapsing cell lines versus wild-type Panc02 were performed revealing an important number of genes (383) whose expression levels were modified more than two-fold. These changes grouped in certain gene ontology categories should harbor the mechanistic explanations of the acquired selective resistance to IFNgamma.

Adenoviridae↗
PubMed2002

A novel strategy for the generation of angiostatic kringle regions from a precursor derived from plasminogen.

In this study we have explored the feasibility of generating angiostatin by incorporating an endoproteolytic furin cleavage site into plasminogen to allow conversion of the precursor molecule into an angiostatic active K1-3 fragment. We show that secretable angiostatin can be successfully generated from cells infected with adenovirus carrying the furin-mutated plasminogen (AdmuthPlgK3). Supernatant from cells transduced with AdmuthPlagK3 inhibits tube formation and proliferation and migration of human umbilical vein endothelial cells with an efficiency similar to that of supernatant from cells infected with adenovirus expressing kringle 1-3 of plasminogen (AdK1-3). Administration of AdmuthPlgK3 and AdK1-3 in mice results in significantly decreased endothelial cell infiltration in VEGF-embedded Matrigel plugs. Treatment with AdmuthPlgK3 and AdK1-3 exerts strong antitumoral effect in models of hepatocellular carcinoma and Lewis lung cancer. This antitumor effect was associated with decreased microvessel density in the tumors. Taken together, our data demonstrate that angiostatin endowed with strong antiangiogenic and antitumor effects can be released from a furin-mutated plasminogen acting as a precursor. This strategy may have potential to develop angiostatic anti-cancer therapies.

Adenoviridae↗
PubMed2001

Gene therapy of orthotopic hepatocellular carcinoma in rats using adenovirus coding for interleukin 12.

The use of gene therapy to enhance antitumor immunity has emerged as a promising procedure to fight cancer. In this study we have tested the ability of an adenovirus carrying interleukin 12 (IL-12) gene (AdCMVIL-12) to eliminate tumoral lesions in 3 animal models of orthotopic hepatocellular carcinoma (HCC). Intratumoral injection of AdCMVIL-12 in animals with a single big tumor nodule implanted in the liver resulted in significant inhibition of tumor growth in a dose-dependent manner. Fifty percent of animals that received a dose of 5 x 10(9) plaque-forming units, showed complete regression of the tumor 2 weeks after treatment. In animals with 2 independent tumor nodules in the left liver lobe, injection in only one of them of 5 x 10(9) pfu AdCMVIL-12 induced, 15 days after therapy, complete regression of 50% of treated tumors and also of 50% of untreated lesions, with 60% long-term survival. Rats that were tumor free after therapy with AdCMVIL-12 showed protection against tumor rechallenge. A group of rats received the carcinogen diethylnitrosamine and developed multiple hepatic dysplasic nodules of 1 to 5 mm in diameter. These animals were treated by intrahepatic artery injection of either AdCMVIL-12 (5 x 10(9) pfu) or control vector. In this model AdCMVIL-12 induced complete tumor regression in 20% of treated rats and inhibited tumor growth in 60% of cases with an increase in rat survival. Activation of natural killer (NK) cells and inhibition of angiogenesis were found to be antitumor mechanisms set in motion by AdCMVIL-12. Our data indicate that experimental HCC can be efficiently treated by intratumoral or intravascular injection of adenovirus expressing IL-12.

Adenoviridae↗
PubMed2001

Adenovirus-mediated CD40 ligand gene therapy in a rat model of orthotopic hepatocellular carcinoma.

Unresectable hepatocellular carcinoma (HCC) lacks effective therapy and entails very poor prognosis. In this study, we have explored a gene-therapeutic approach to stimulate antitumor immunity by adenoviral-mediated transfer of CD40 ligand to treat HCC in rats. In vitro infection of a rat HCC cell line (McA-RH7777) with adenoviral vector expressing CD40 ligand (AdCMVmCD40L) induced CD40L expression in a dose-dependent manner. Expression of CD40L in McA-RH7777 cells did not alter their growth rate in vitro, but it abrogated their tumorigenicity when CD40L-expressing cells were implanted into the liver of syngenic Buffalo rats. In vivo gene therapy of established orthotopic HCC nodules (6.5 mm in diameter) in Buffalo rats by intratumor injection of AdCMVmCD40L vector led to complete tumor eradication and long-term survival in 69.5% of treated animals. Therapy with AdCMVmCD40L induced strong lymphocytic infiltration of the tumoral tissue and increased apoptosis of malignant cells. The observed antitumoral effect was mediated by CD8(+) T cells and was associated with increased interleukin (IL)-12 serum levels and enhanced natural killer (NK) activity. Animals that eliminated the tumor after in vivo gene therapy developed protective antitumor immunity being resistant to rechallenge with neoplastic cells. Toxicity of the therapy with AdCMVmCD40L was slight, with only a transient increase in the level of serum transaminases and minor lymphocyte infiltration of normal liver tissue. These data demonstrate that intratumoral administration of AdCMVmCD40L may provide an efficient and safe treatment for HCC.

Adenoviridae↗
PubMed2000

Intratumoral coinjection of two adenoviruses, one encoding the chemokine IFN-gamma-inducible protein-10 and another encoding IL-12, results in marked antitumoral synergy.

We have constructed a recombinant defective adenovirus that expresses functional murine IFN-gamma-inducible protein-10 (IP-10) chemokine (AdCMVIP-10). Injection of AdCMVIP-10 into s.c. tumor nodules derived from the CT26 murine colorectal adenocarcinoma cell line displayed some antitumor activity but it was not curative in most cases. Previous studies have shown that injection of similar s. c. CT26 tumor nodules with adenovirus-encoding IL-12 (AdCMVIL-12) induces tumor regression in nearly 70% of cases in association with generation of antitumor CTL activity. AdCMVIP-10 synergizes with the antitumor effect of suboptimal doses of AdCMVIL-12, reaching 100% of tumor eradication not only against injected, but also against distant noninjected tumor nodules. Colocalization of both adenoviruses at the same tumor nodule was required for the local and distant therapeutic effects. Importantly, intratumoral gene transfer with IL-12 and IP-10 generated a powerful tumor-specific CTL response in a synergistic fashion, while both CD4 and CD8 T cells appeared in the infiltrate of regressing tumors. Moreover, the antitumor activity of IP-10 plus IL-12 combined gene therapy was greatly diminished by simultaneous in vivo depletion of CD4+ and CD8+ T cells but was largely unaffected by single depletion of each T cell subset. An important role for NK cells was also suggested by asialo GM1 depletion experiments. From a clinical point of view, the effects of IP-10 permit one to lower the required gene transfer level of IL-12, thus preventing dose-dependent IL-12-mediated toxicity while improving the therapeutic efficacy of the elicited antitumor response.

Adenoviridae↗
PubMed2000

Adenoviral gene transfer of interleukin 12 into tumors synergizes with adoptive T cell therapy both at the induction and effector level.

Tumors infected with a recombinant defective adenovirus expressing interleukin 12 (IL-12) undergo regression, associated with a cytotoxic T lymphocyte (CTL)-mediated antitumor immune response. In the present study we generated anti-CT26 CTLs by short-term coculture of CT26 cells and lymph node cells obtained from mice harboring subcutaneous CT26 tumors injected with an adenoviral vector expressing IL-12 (AdCMVIL-12), control adenovirus (AdCMVlacZ), or saline. Regression of small intrahepatic CT26 tumors in unrelated syngeneic animals was achieved with CTLs derived from mice whose subcutaneous tumors had been injected with AdCMVIL-12 but not with CTLs from the other two control groups. The necessary and sufficient effector cell population for adoptive transfer consisted of CD8+ T cells that showed anti-CT26 specificity partly directed against the AH1 epitope presented by H-2Ld. Interestingly, treatment of a subcutaneous tumor nodule with AdCMVIL-12, combined with intravenous adoptive T cell therapy with short-term CTL cultures, had a marked synergistic effect against large, concomitant live tumors. Expression of IL-12 in the liver in the vicinity of the hepatic tumor nodules, owing to spillover of the vector into the systemic circulation, appeared to be involved in the increased in vivo antitumor activity of injected CTLs. In addition, adoptive T cell therapy improved the outcome of tumor nodules transduced with suboptimal doses of AdCMVIL-12. Our data provide evidence of a strong synergy between gene transfer of IL-12 and adoptive T cell therapy. This synergy operates both at the induction and effector phases of the CTL response, thus providing a rationale for combined therapeutic strategies for human malignancies.

Adenoviridae↗
PubMed2000

In vivo gene transfer of CD40 ligand into colon cancer cells induces local production of cytokines and chemokines, tumor eradication and protective antitumor immunity.

The interaction between CD40 ligand (CD40L, CD154) and its receptor CD40 on antigen-presenting cells, is essential for the initiation of cell-mediated and humoral immune responses. In this study, we investigated the antitumor effect of in vivo gene transfer of CD40L to tumor cells using an adenoviral vector (AdCMVmCD40L) in a murine CT-26 colon cancer model. We found that injection of AdCMVmCD40L caused tumor regression in a dose-dependent manner. A complete regression of tumor was observed in 81% of mice treated with 10(9) p.f.u. of AdCMVmCD40L. The antitumor effect induced by CD40L was mediated by CD8+ T cells and was associated with the generation of tumor-specific cytolytic T lymphocytes (CTL). Animals that eradicated the tumor were protected against tumor cell rechallenge, and both CD4+ and CD8+ T cells were involved in specific protective immunity. Treatment with AdCMVmCD40L in one tumor nodule also caused complete regression of established tumors at distant sites. The antitumor effect elicited by AdCMVmCD40L was associated with the intratumoral production of IL-12 and IFN-gamma and with an increased intratumoral expression of chemokines such as MIP- 1alpha, MIP-1beta, MIP-2, RANTES, and eotaxin. These data demonstrate that intratumoral injection of AdCMVmCD40L induces a powerful cascade of chemokines and cytokines in the tumor mass and stimulates an efficient antitumor immunity leading to regression of established colon cancer and protection against tumor cell rechallenge.

Adenoviridae↗
PubMed1991

Twenty-four-hour controlled substance documentation system: the optimal way to monitor use in the nursing units.

Accountability for the use of controlled substances in the nursing units is a top priority for nursing and pharmacy administration in any health-care institution. After several discrepancies were found in inventory at the John F. Kennedy Memorial Hospital in Indio, California, the pharmacy department revised the controlled substance handling system in the hospital and implemented a 24-hour controlled substance recording system. The system provided greater accountability and allowed follow-up on any discrepancy within the next shift. The system has been highly successful. There had been six discrepancies in 12 months before implementing the system. There has been no incident of discrepancy in the last 31 months. The authors conclude that 24-hour controlled substance documentation system is very effective in providing greater accountability and control over controlled substance use in the nursing units.

California↗
PubMed1991

Atropine intoxication from the ingestion and smoking of jimson weed (Datura stramonium).

Anticholinergic effects occur due to jimson weed intoxication. The most common intoxication involves teenagers desiring mind-altering properties from the plant. We report 4 cases of jimson weed intoxication due to ingestion and inhalation (smoking) of jimson weed. Clinicians should be aware of the potential abuse of botanicals such as jimson weed.

Adolescent↗
PubMed1991

Probable anaphylactic reaction to corn-derived dextrose solution.

Secondary to the i.v. administration of a corn-derived dextrose solution, a 23-y-old pregnant female patient admitted to the hospital at term gestation developed an anaphylactic reaction. Orofacial swelling, difficulty in breathing, hypotension, cardiac arrhythmia, voice hoarseness, total body warmth and flushing occurred within 8 min of initiation of a 5% dextrose Lactated Ringer's solution. The i.v. solution was discontinued and plain lactated Ringer's solution was begun with no sequelae. The patient delivered a viable male infant with a post-operative course being unremarkable. A sample of suspect solution was sent to the manufacturer but no contamination was reported. Although the reaction elicited in this patient was rare, clinicians should be aware of the possibility of corn allergy due to the administration of i.v. fluids containing corn-derived dextrose.

Adult↗
PubMed1989

1988 Joint Commission survey in a community hospital.

JCAHO is increasingly emphasizing the importance of quality patient care and has recently mandated the involvement of pharmacy to help optimize patient care. To comply with the JCAHO requirements, the pharmacy department must develop standards and protocols that are ultimately designed to improve patient care. This article describes how we optimized patient care by complying with the JCAHO standards and prepared for the survey.

Accreditation↗