Bruce Ng - Profile on Academia.edu (original) (raw)
Papers by Bruce Ng
Pre-treatment radiological factors associated with poor functional outcome in an Asian cohort of large vessel occlusion acute ischemic stroke patients undergoing mechanical thrombectomy
Frontiers in neurology, Jun 26, 2024
American Journal of Pathology, Mar 1, 2005
Cellular interaction with the extracellular matrix is thought to be a critical event in controlli... more Cellular interaction with the extracellular matrix is thought to be a critical event in controlling angiogenesis and tumor growth. In our previous studies, genetically distinct noncollagenous (NC) domains of type-IV collagen were shown to interact with integrin receptors expressed on the surface of endothelial cells. Moreover, these NC1 domains were shown to inhibit angiogenesis in vivo. Here, we provide evidence that a recombinant form of the ␣2(IV)NC1 domain of type-IV collagen could bind integrins ␣11 and ␣v3 expressed on melanoma cells and inhibit tumor cell adhesion in a ligand-specific manner. Systemic administration of recombinant ␣2(IV)NC1 domain potently inhibited M21 melanoma tumor growth within full thickness human skin and exhibited a dose-dependent inhibition of tumor growth in nude mice. Interestingly, ␣2(IV)NC1 domain enhanced cellular senescence in tumor cells in vitro and in vivo. Taken together, these results suggest that recombinant ␣2(IV)NC1 domain is not only a potent anti-angiogenic reagent, but it also directly impacts tumor cell behavior. Thus, ␣2(IV)NC1 domain represents a potent inhibitor of tumor growth by impacting both endothelial and tumor cell compartments.
Isolated lung perfusion with FUDR is an effective treatment for colorectal adenocarcinoma lung metastases in rats
The Annals of Thoracic Surgery, 1995
Currently, the only treatment capable of significantly prolonging survival in patients with isola... more Currently, the only treatment capable of significantly prolonging survival in patients with isolated pulmonary metastases from colorectal adenocarcinoma is complete resection. Systemic chemotherapy has been shown to provide little benefit. We evaluated the efficacy of highdose, organ-specific 2'-deoxy-5-fluorouridine (FUDR) using a model of isolated single-lung perfusion (ILP) in the rat. On day 0, 28 BDIX rats were inoculated intravenously with 10(6) viable Sp-5 colorectal adenocarcinoma cells. On day 10 after-tumor inoculation, animals were randomized into five treatment groups. Group I received a continuous intravenous infusion of FUDR (1 mg.kg-1.d-1) for 7 days administered by an osmotic minipump. Group II underwent isolated left lung perfusion with a buffered Hespan solution, groups III to V underwent ILP with 3.5, 7, and 14 mg of FUDR per milliliter of the buffered Hespan solution, respectively. Animals undergoing ILP were anesthetized with pentobarbital, intubated, and ventilated, and then underwent left thoracotomy with cannulation of the pulmonary artery; the pulmonary artery and vein were clamped proximally. Groups II to V were perfused for 20 minutes at a rate of 1 mL/min, followed by a 5-minute washout with FUDR-free buffered Hespan solution. On day 26 after tumor inoculation, the animals in all groups were sacrificed and their lungs were stained and counted. Animals that underwent ILP with 14 mg of FUDR per milliliter of the buffered Hespan solution showed a significant decrease in the number of tumor nodules on the treated side versus the number on the untreated side (455.2 +/- 87.3 versus 11 +/- 6.4; p < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)
Para-Aminobenzoic Acid (PABA) enhances responses to low and high dose rate radiotherapy (RT) in glioblastoma cell lines
586 Objective: Glioblastoma multiforme is the most common primary brain tumor in adults. Median s... more 586 Objective: Glioblastoma multiforme is the most common primary brain tumor in adults. Median survival is approximately one year with surgical resection and postoperative RT, and is improved by three months with the addition of the alkylating agent temozolomide (TMZ). Additional therapeutic developments are urgently needed to improve the dismal outcome of this disease. Recent studies show that radiation delivery with Tomotherapy, at dose rates 4-5 times higher compared to conventional techniques, enhance cell killing. In addition, we have shown that PABA enhances RT responses in various cancers both in-vitro and in-vivo. In this study, we investigate the impact of dose rate and PABA in three high-grade glioma cell lines as a function of their resistance to RT and alkylating damage. Materials and Methods: T98G (radiation/TMZ resistant), U118, and U87MG, were irradiated to give total doses of 6, 12 and 18 Gy via two dose rates; low dose rate (LDR) of 100 cGy/min and high dose rate (HDR) of 2200cGy/min. Cells were synchronized by serum starving prior to treatment. PABA (100 ug/mL) was added at 6 hrs prior and for 96 hrs after RT. TMZ exposure (100uM) was for 7 days. Modified MTT (performed 96 hours post RT) and clonogenic assays were performed. Results: When compared to LDR, HDR increased growth inhibition (GI) across all cell lines and dose groups. Specifically, in radioresistant T98G cells, HDR resulted in a 100% (6Gy), 54% (12 Gy) and 13% (18 Gy) increase in cell death compared to LDR. The addition of PABA to LDR augmented GI in all cell lines by 68-146% (6 Gy), 50-82% (12 Gy) and 7-37% (18 Gy). This GI was greater or equal to that observed with HDR alone. For the HDR group, the addition of PABA resulted in a more moderate increase in GI by 7-46% (6 Gy) and 10-36% (12 Gy). With TMZ alone and no RT, GI rates were 26% (T98G), 75% (U118) and 90% (U87MG). With PABA alone and no RT, GI rates were 57% (T98G), 55% (U118) and 73% (U87MG). The combination of PABA and TMZ with no RT increased GI to 52% only in the TMZ-resistant T98G cells. Conclusions: PABA enhances radiation responses both with LDR and HDR radiation. HDR radiation improves cell killing in all three cell lines. Without RT, PABA alone or in combination with TMZ doubles tumor GI in TMZ-resistant cells. This is the first in-vitro study to demonstrate modulation of radiation responses with LDR and HDR RT and show significant PABA modulation at LDR in glioblastoma cells. Currently, we are combining pre-treatment with PABA and TMZ followed by HDR and LDR RT in these and other glioblastoma cell lines. p21 and key signaling pathways are being examined by Western Blot, and apoptotic responses are being assessed. With the clinical availability of Tomotherapy, it becomes relevant to further study the mechanism of action of this combined therapy and assess the role of PABA as potential adjuvant to RT in malignant brain tumors. Supported in part by The Chemotherapy Foundation and Cancer Innovations, Inc.
PubMed, Nov 15, 1993
Cachexia and malnutrition play a significant role in the morbidity associated with antineoplastic... more Cachexia and malnutrition play a significant role in the morbidity associated with antineoplastic chemotherapy regimens. Conventional nutritional support during cancer therapy has shown little benefit in terms of reducing morbidity and mortality. We examined the anabolic properties of growth hormone (GH) that preserve normal body composition in sarcoma-bearing animals treated with doxorubicin. On day 0, 40 male Fischer 344 rats were inoculated with 10(6) methylcholanthrene-induced sarcoma cells s.c. in the left flank. On day 9, animals were randomized into 3 groups: control (CTL, n = 13); doxorubicin (DOX, n = 13); and doxorubicin plus GH (DOX-GH, n = 14). Two CTL animals were excluded due to tumor invasion into the peritoneal cavity. From day 9 to day 23, the DOX-GH group received daily s.c. recombinant rat GH injection (1 mg/kg). On day 13, DOX and DOX-GH groups received 7 mg/kg of DOX i.v. while the CTL group received sham i.v. sterile saline injection. Body weight and tumor dimensions were measured daily. On day 23, all animals were weighed and sacrificed. Tumors were resected and weighed. Body composition analysis was performed. Plasma GH levels were measured by radioimmunoassay and insulin growth factor 1 levels were measured by chondrocyte proliferation bioassay. The DOX-GH group had a significantly higher mean body weight, carcass weight, total fat free body mass, insulin growth factor 1, and GH plasma levels as compared to the DOX group. No difference in total food intake was observed between the DOX and DOX-GH groups. There was no difference in final tumor weight and tumor growth rate between DOX and DOX-GH groups. Exogenous growth hormone can attenuate weight loss and preserve host body composition in tumor-bearing rats treated with doxorubicin without stimulating tumor growth.
The Annals of Thoracic Surgery, Sep 1, 1995
Background. Isolated single-lung perfusion with doxorubicin hydrochloride was shown to be effecti... more Background. Isolated single-lung perfusion with doxorubicin hydrochloride was shown to be effective in clearing experimental sarcoma lung metastases in the rat. The best perfusate to be used for isolated lung perfusion and factors affecting the final lung concentration of doxorubicin are the subject of the present study. In experiment 1, 60 animals were randomized to undergo isolated left lung perfusion with doxorubicin with six different perfusates (n = 10 per group): saline, low-potassium-dextran, 5% albumin, 6% hetastarch, 5~/, buffered albumin, and 6% buffered hetastarch. Five animals served as negative controls. After perfusion, the lung wet to dry ratio and final lung doxorubicin concentration were determined. In experiment 2, 60 animals underwent isolated left lung perfusion with either 80 /~g/mL or 320 /~g/mL of doxorubicin. Animals were perfused at either 0.5 mL/min or 1 mL/min and for 2, 6, or 10 minutes. At the end of the perfusion period, the left lung doxorubicin concentration was measured. Statistical analysis included analysis of variance, the Duncan test for multiple comparisons, and multiple linear regression analysis. Significance was defined as a p value of less than 0.05.
PubMed, Aug 1, 2002
Treatment with the proteasome inhibitor, PS-341 resulted in concentration- and time-dependent eff... more Treatment with the proteasome inhibitor, PS-341 resulted in concentration- and time-dependent effects on Bcl-2 phosphorylation and cleavage in H460 cells that coincided with the PS-341-induced G2-M phase arrest. The observed Bcl-2 cleavage paralleled the degree of PS-341-induced apoptosis but was detected to a similar extent with comparable concentrations of two other proteasome inhibitors (MG-132 and PSI). Calpain inhibitors, ALLM and ALLN, and the caspase inhibitors, Z-VAD and AC-YVAD did not induce BcI-2 phosphorylation and cleavage. Exposure to PS-341 resulted in an additional Mr 25,000 cleavage fragment of Bcl-2, whereas only a Mr 23,000 fragment was observed with other anticancer agents. The formation of the Mr 25,000 fragment was not prevented by caspase inhibitors unlike the Mr 23,000 fragment, which suggests mediation by a caspase-independent pathway. Cell fractionation studies revealed that the Bcl-2 cleaved fragments localize within membrane structures and was an early event (at approximately 12 h, posttreatment), and before the observed cleavage of poly(ADP-ribose) polymerase (PARP), beta-catenin, and DNA fragmentation (at approximately 36 h posttreatment). The Mr 23,000 Bcl-2 cleavage product was inhibited by the pan-caspase inhibitor and the inhibitors of capase-3, -8, -9; but the PARP cleavage was prevented only by the pan-caspase and caspase-3 inhibitors, which suggests that the Mr 23,000 Bcl-2 cleavage occurred at both the initiation and execution stages of apoptosis. The inhibition of the ubiquitin/proteasome pathway by PS-341 leads, at an early stage of apoptosis, to Bcl-2 phosphorylation and a unique proteolytic cleavage product, which are associated with G2-M phase arrest and the induction of apoptosis.
International Journal of Radiation Oncology Biology Physics, Mar 1, 2004
Ionizing radiation can reduce tumor growth outside the field of radiation, known as the abscopal ... more Ionizing radiation can reduce tumor growth outside the field of radiation, known as the abscopal effect. Although it has been reported in multiple malignancies, the abscopal effect remains a rare and poorly understood event. Ionizing radiation generates inflammatory signals and, in principle, could provide both tumor-specific antigens from dying cells and maturation stimuli that are necessary for dendritic cells' activation of tumorspecific T cells. We therefore tested the hypothesis that the abscopal effect elicited by radiation is immune mediated. This was directly tested by enhancing the number of available dendritic cells using the growth factor Flt3-Ligand (Flt3-L). Methods and Materials: Mice bearing a syngeneic mammary carcinoma, 67NR, in both flanks were treated with Flt3-L daily for 10 days after local radiation therapy (RT) to only 1 of the 2 tumors at a single dose of 2 or 6 Gy. The second nonirradiated tumor was used as indicator of the abscopal effect. Data were analyzed using repeated measures regression. Results: RT alone led to growth delay exclusively of the irradiated 67NR tumor, as expected. Surprisingly, growth of the nonirradiated tumor was also impaired by the combination of RT and Flt3-L. As control, Flt3-L had no effect without RT. Importantly, the abscopal effect was shown to be tumor specific, because growth of a nonirradiated A20 lymphoma in the same mice containing a treated 67NR tumor was not affected. Moreover, no growth delay of nonirradiated 67NR tumors was observed when T cell deficient (nude) mice were treated with RT plus Flt3-L. Conclusions: These results demonstrate that the abscopal effect is in part immune mediated and that T cells are required to mediate distant tumor inhibition induced by radiation.
Clinical Cancer Research, Sep 30, 2008
Purpose: Extracellular matrix remodeling during tumor growth plays an important role in angiogene... more Purpose: Extracellular matrix remodeling during tumor growth plays an important role in angiogenesis. Our preclinical data suggest that a newly identified cryptic epitope (HU177) within collagen type IV regulates endothelial and melanoma cell adhesion in vitro and angiogenesis in vivo. In this study, we investigated the clinical relevance of HUI77 shedding in melanoma patient sera. Experimental Design: Serum samples from 291 melanoma patients prospectively enrolled at the New York University Medical Center and 106 control subjects were analyzed for HU177 epitope concentration by a newly developed sandwich ELISA assay. HU177 serum levels were then correlated with clinical and pathologic parameters. Results: Mean HU177 epitope concentration was 5.8 ng/mL (range, 0-139.8 ng/mL). A significant correlation was observed between HU177 concentration and nodular melanoma histologic subtype [nodular, 10.3 F 1.6 ng/mL (mean F SE); superficial spreading melanoma, 4.5 F 1.1ng/mL; all others, 6.1 F2.1ng/mL; P = 0.01byANOVA test]. Increased HU177 shedding also correlated with tumor thickness (V1.00 mm, 3.8 F 1.1 ng/mL ; 1.01-3.99 mm, 8.7 F 1.3 ng/mL; z4.00 mm, 10.3 F 2.4 ng/mL; P = 0.003 by ANOVA). After multivariate analysis controlling for thickness, the correlation between higher HU177 concentration and nodular subtype remained significant (P = 0.03). The mean HU177 epitope concentration in control subjects was 2.4 ng/mL. Conclusions: We report that primary melanoma can induce detectable changes in systemic levels of cryptic epitope shedding. Our data also support that nodular melanoma might be biologically distinct compared with superficial spreading type melanoma. As targeted interventions against cryptic collagen epitopes are currently undergoing phase I clinical trial testing, these findings indicate that patients with nodular melanoma may be more susceptible to such targeted therapies.
Correlation of shedding cryptic epitope (HU177) levels and treatment response in sera of melanoma patients
Journal of Clinical Oncology, May 20, 2008
20018 Background: We have previously shown that shedding of the recently identified cryptic epito... more 20018 Background: We have previously shown that shedding of the recently identified cryptic epitope HU177 can be measured in melanoma patients’ sera and correlates with invasiveness of primary melanomas. Here we prospectively measured HU177 collagen epitope (HCE) titers in sera of stage IV melanoma patients (pts) enrolled in two clinical trials conducted at our institution. Methods: Serum samples from 37 pts (11-M1a, 10-M1bM, 16-M1c) who received Sorafenib on an NCI phase II trial (6617) (study A) and from 18 stage IV pts who were treated 2nd line with Carboplatin, Paclitaxel, and PABA on a phase I trial (study B), were analyzed for HCE by a dual sandwich ELISA during each of up to 12 cycles. Serum was aliquoted into 200 μl volumes and stored at - 20°C until assayed. Correlation of HCE levels with treatment response as measured by PET/CT or CT imaging was examined. Results: In 2 of 3 radiographically responding pts in study A correlation with HCE was seen. In one pt, HCE levels dropped from 74.4 ng/ml to ...
Bortezomib with Taxanes
Humana Press eBooks, 2004
We have examined the use of combinations of bortezomib (PS-341) with docetaxel in in vitro and in... more We have examined the use of combinations of bortezomib (PS-341) with docetaxel in in vitro and in vivo studies and have added the use of localized delivery of radiation in in vitro combinations through the use of a 90Y-labeled monoclonal antibody, BrE-3. In in vitro studies, marked cytotoxic effects from the combination of PS-341/docetaxel were seen progressively with the ovarian cell line SKOV3 over the time period of 24–72 h, with additive activity at 48 h and synergistic activity at 72 h. In non-small cell lung cancer (H460 cell) PS-341 induced a 25-kDa Bcl-2 cleavage product different from fragments produced by other anticancer agents. This unique Bcl-2 cleavage product was an early event starting 12 h after PS-341 exposure, followed by DNA fragmentation and cleavage of caspase-mediated PARP and β-catenin at 36 h. Results with ovarian xenograft model showed the beneficial effects of combined treatment with PS-341 and docetaxel: tumor growth was limited for a 30-d period following the cessation of treatment compared with single agents alone. Significant augmentation of cytotoxicity at and below therapeutic levels of PS-341 and docetaxel were observed with radioimmunotherapy studies using ovarian and breast cancer cell lines.
Systemic anti-cancer effects are triggered by local treatment with ionizing radiation and FLT3-Ligand in a syngeneic mouse model of mammary carcinoma
International Journal of Radiation Oncology Biology Physics, Oct 1, 2002
Para-aminobenzoic acid (PABA) enhances the in-vitro tumor response of ovarian cancer to Topotecan (TTN) through mitochondrial-mediated apoptosis
Cancer Research, May 1, 2005
Molecular Therapy, 2011
Jak Inhibitors Mitigate Lipid-siRNA Toxicities lysate assay (Lonza, Basel, Switzerland). In all L... more Jak Inhibitors Mitigate Lipid-siRNA Toxicities lysate assay (Lonza, Basel, Switzerland). In all LNP-siRNA preparations used in our animal studies, the endotoxin levels at the highest dose of LNP05-siRNA were <0.25 EU/kg (body weight), significantly below the endotoxin release limit for humans (5 EU/kg), defined by US Food and Drug Administration and World Health Organization.
A simplified method for endotracheal intubation in the rat
Journal of Applied Physiology, Apr 1, 1994
Endotracheal intubation in small laboratory animals is often necessary for survival experiments. ... more Endotracheal intubation in small laboratory animals is often necessary for survival experiments. Methods of airway control have included tracheostomy, blind intubation, and intubation under direct vision. Most of these methods are unsatisfactory and associated with high failure and complication rate. We developed an easy method of endotracheal intubation in the rat that requires simple material that is easily available to any research facility. The animals were anesthetized with pentobarbital sodium, the tongue was pulled out, and an otoscope was introduced into the oropharynx. By direct vision, a guide wire was inserted into the trachea and a 16-gauge intravenous catheter was glided over the wire. The first group of 70 rats underwent left thoracotomy with endotracheal intubation and mechanical ventilation at our laboratory as part of a study on isolated lung perfusion. The second group of five rats was anesthetized with pentobarbital, and a left carotid catheter and an endotracheal tube were inserted. Animals were ventilated with 100% O2. Arterial blood gases were sampled before intubation, 30 min after ventilation, and 60 min after extubation. In the first group, 94.3% (66 of 70) of the animals survived surgery and mortality was not directly related to the intubation and/or ventilation. All five animals of the second group survived the procedure to be extubated. Arterial PO2 before intubation, 30 min after intubation and ventilation, and 60 min after extubation was 77.1 +/- 8.5, 465.0 +/- 55.6, and 98.9 +/- 12.8 Torr, respectively. PCO2 at the same time points was 42.5 +/- 10.1, 35.1 +/- 6.3, and 32.7 +/- 6.5 Torr, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
The Annals of Thoracic Surgery, Aug 1, 1993
Unilateral pulmonary artery occlusion inhibits growth of metastatic sarcoma in the rat lung
Journal of Surgical Oncology, Nov 1, 1994
Tumors depend on their blood supply for growth. The blood supply to metastatic neoplasia of lung ... more Tumors depend on their blood supply for growth. The blood supply to metastatic neoplasia of lung is usually from the pulmonary circulation or both the pulmonary and systemic circulation. The antineoplastic effect of pulmonary artery occlusion was investigated in a rat model of methylcholanthrene‐induced metastatic pulmonary sarcoma. Left pulmonary artery ligation was performed on day 7 after tumor inoculation, and animals were sacrificed on day 14. The tumor burden of the left lung decreased 44% when compared with the control group. The survival of non‐tumor‐bearing rats undergoing left pulmonary artery ligation for 24 hours followed by right pneumonectomy after 2 weeks was also studied. No significant lung damage after a period of left pulmonary artery ligation was seen, as evidenced by both survival after contralateral right pneumonectomy and histology. Balloon occlusion of pulmonary artery, together with regional chemotherapy for patients with lung metastases, may warrant investigation. © 1994 Wiley‐Liss, Inc.
Establishment of an Experimental Intrapulmonary Tumor Nodule Model
The Annals of Thoracic Surgery, Jul 1, 1997
A pulmonary tumor model is necessary to study the biology and therapy of lung cancer. Methods to ... more A pulmonary tumor model is necessary to study the biology and therapy of lung cancer. Methods to establish a solitary intrapulmonary nodule are not well defined. Two methods for solitary intrapulmonary tumor nodule development in the Fischer rat are described. Methylcholanthrene-induced sarcoma cell suspensions were introduced into lung parenchyma of Fischer rats via limited thoracotomy and lung puncture, or instilled into a distal airway after tracheal puncture and catheterization. Intrapulmonary tumor location, implantation mortality, procedure length, and animal survival were recorded. Single pulmonary nodules developed at the implanted position in 100% (n = 320) and 95% (62/65) of animals after direct injection into the pulmonary parenchyma or via tracheal puncture and instillation. Operative mortality was 2% and 5% via lung or tracheal implantation, respectively. Less than 5 minutes was required for each implantation. Mean survival time was 24 +/- 2 and 26 +/- 6 days after lung or tracheal implantation in animals allowed to survive until tumor-induced death. These easily performed, reproducible methods of establishing solitary intrapulmonary tumors are useful tools for lung cancer research.
Specific organ gene transfer in vivo by regional organ perfusion with herpes viral amplicon vectors: Implications for local gene therapy
Surgery, Mar 1, 2001
Many gene therapy strategies would benefit from efficient, regional organ delivery of therapeutic... more Many gene therapy strategies would benefit from efficient, regional organ delivery of therapeutic genes. Regional perfusions of lung, liver, or bladder were performed to determine if rapid and efficient gene transfer can be accomplished in vivo, and to determine if in vivo gene transfer can be limited to the organ of interest. In addition, herpes simplex virus tumor necrosis factor (HSVtnf), carrying the human tumor necrosis factoralpha gene was used as a treatment for methylcholanthrene sarcoma in a syngeneic lung metastases model in Fisher rats. A 20-minute perfusion using HSV carrying beta-galactosidase (HSVlac) produced significant expression of this marker gene isolated to the target organs, without organ-specific tissue injury or inflammation. Regional perfusion of organs with HSV carrying the cytokine gene tumor necrosis factor alpha also resulted in high-level local organ production of this cytokine (2851 +/- 53 pg/g tissue in perfused lung versus 0 for the contralateral lung). For the current vector construct, expression of the gene of interest peaked between 2 and 4 days and was undetectable by 2 weeks after perfusion. In animals undergoing perfusion as treatment for pulmonary sarcoma, there was no difference between tumor counts in lungs perfused with HSVlac (17 +/- 6) or HSVtnf (22 +/- 8), but either treatment resulted in lower tumor counts than controls (111 +/- 24 nodules per lung, P <.02). Regional organ perfusion using herpes viral vectors is an effective and well-tolerated in vivo method of transiently delivering potentially toxic gene products to target organs in directing gene therapy. Regional lung perfusion with HSV amplicons reduces tumor burden in a rat model of pulmonary metastases, though HSVtnf cannot be demonstrated to augment the cytopathic effect of the HSV amplicon alone in the current model.
Annals of Surgical Oncology, Jul 1, 1994
Background: The relative effects of growth hormone on tumor versus host growth and protein metabo... more Background: The relative effects of growth hormone on tumor versus host growth and protein metabolism are not known. This study examines the influence of recombinant rat growth hormone (r-rGH) on host and tumor growth, host body composition, and protein synthesis of tumor and host in tumorbearing rats. Methods: After left flank implantation of methylcholanthrene-induced sarcoma, 28 Fischer rats with palpable tumor were treated with s.c. saline or 1 mg/kg/day r-rGH for 11 days. At death, fractional protein synthetic rates (FSRs) of tumor, liver, and gastrocnemius muscle were determined. In a separate experiment, 27 tumor-bearing rats received saline or 1 mg/kg/day r-rGH for 2 weeks. Tumor and host growth and host body composition were analyzed. Results: Animals treated with r-rGH had significantly higher liver FSR than did controls (233-+ 27%/day vs. 110-+ 4%/day, respectively). No significant differences were associated with growth hormone administration with respect to tumor growth, host composition, or FSR of tumor or muscle. Conclusions: Growth hormone stimulates liver protein synthesis, without changing tumor growth, protein synthesis, or host composition in this rat sarcoma model. Further investigation of growth hormone as an anticachectic agent is warranted.
Pre-treatment radiological factors associated with poor functional outcome in an Asian cohort of large vessel occlusion acute ischemic stroke patients undergoing mechanical thrombectomy
Frontiers in neurology, Jun 26, 2024
American Journal of Pathology, Mar 1, 2005
Cellular interaction with the extracellular matrix is thought to be a critical event in controlli... more Cellular interaction with the extracellular matrix is thought to be a critical event in controlling angiogenesis and tumor growth. In our previous studies, genetically distinct noncollagenous (NC) domains of type-IV collagen were shown to interact with integrin receptors expressed on the surface of endothelial cells. Moreover, these NC1 domains were shown to inhibit angiogenesis in vivo. Here, we provide evidence that a recombinant form of the ␣2(IV)NC1 domain of type-IV collagen could bind integrins ␣11 and ␣v3 expressed on melanoma cells and inhibit tumor cell adhesion in a ligand-specific manner. Systemic administration of recombinant ␣2(IV)NC1 domain potently inhibited M21 melanoma tumor growth within full thickness human skin and exhibited a dose-dependent inhibition of tumor growth in nude mice. Interestingly, ␣2(IV)NC1 domain enhanced cellular senescence in tumor cells in vitro and in vivo. Taken together, these results suggest that recombinant ␣2(IV)NC1 domain is not only a potent anti-angiogenic reagent, but it also directly impacts tumor cell behavior. Thus, ␣2(IV)NC1 domain represents a potent inhibitor of tumor growth by impacting both endothelial and tumor cell compartments.
Isolated lung perfusion with FUDR is an effective treatment for colorectal adenocarcinoma lung metastases in rats
The Annals of Thoracic Surgery, 1995
Currently, the only treatment capable of significantly prolonging survival in patients with isola... more Currently, the only treatment capable of significantly prolonging survival in patients with isolated pulmonary metastases from colorectal adenocarcinoma is complete resection. Systemic chemotherapy has been shown to provide little benefit. We evaluated the efficacy of highdose, organ-specific 2'-deoxy-5-fluorouridine (FUDR) using a model of isolated single-lung perfusion (ILP) in the rat. On day 0, 28 BDIX rats were inoculated intravenously with 10(6) viable Sp-5 colorectal adenocarcinoma cells. On day 10 after-tumor inoculation, animals were randomized into five treatment groups. Group I received a continuous intravenous infusion of FUDR (1 mg.kg-1.d-1) for 7 days administered by an osmotic minipump. Group II underwent isolated left lung perfusion with a buffered Hespan solution, groups III to V underwent ILP with 3.5, 7, and 14 mg of FUDR per milliliter of the buffered Hespan solution, respectively. Animals undergoing ILP were anesthetized with pentobarbital, intubated, and ventilated, and then underwent left thoracotomy with cannulation of the pulmonary artery; the pulmonary artery and vein were clamped proximally. Groups II to V were perfused for 20 minutes at a rate of 1 mL/min, followed by a 5-minute washout with FUDR-free buffered Hespan solution. On day 26 after tumor inoculation, the animals in all groups were sacrificed and their lungs were stained and counted. Animals that underwent ILP with 14 mg of FUDR per milliliter of the buffered Hespan solution showed a significant decrease in the number of tumor nodules on the treated side versus the number on the untreated side (455.2 +/- 87.3 versus 11 +/- 6.4; p < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)
Para-Aminobenzoic Acid (PABA) enhances responses to low and high dose rate radiotherapy (RT) in glioblastoma cell lines
586 Objective: Glioblastoma multiforme is the most common primary brain tumor in adults. Median s... more 586 Objective: Glioblastoma multiforme is the most common primary brain tumor in adults. Median survival is approximately one year with surgical resection and postoperative RT, and is improved by three months with the addition of the alkylating agent temozolomide (TMZ). Additional therapeutic developments are urgently needed to improve the dismal outcome of this disease. Recent studies show that radiation delivery with Tomotherapy, at dose rates 4-5 times higher compared to conventional techniques, enhance cell killing. In addition, we have shown that PABA enhances RT responses in various cancers both in-vitro and in-vivo. In this study, we investigate the impact of dose rate and PABA in three high-grade glioma cell lines as a function of their resistance to RT and alkylating damage. Materials and Methods: T98G (radiation/TMZ resistant), U118, and U87MG, were irradiated to give total doses of 6, 12 and 18 Gy via two dose rates; low dose rate (LDR) of 100 cGy/min and high dose rate (HDR) of 2200cGy/min. Cells were synchronized by serum starving prior to treatment. PABA (100 ug/mL) was added at 6 hrs prior and for 96 hrs after RT. TMZ exposure (100uM) was for 7 days. Modified MTT (performed 96 hours post RT) and clonogenic assays were performed. Results: When compared to LDR, HDR increased growth inhibition (GI) across all cell lines and dose groups. Specifically, in radioresistant T98G cells, HDR resulted in a 100% (6Gy), 54% (12 Gy) and 13% (18 Gy) increase in cell death compared to LDR. The addition of PABA to LDR augmented GI in all cell lines by 68-146% (6 Gy), 50-82% (12 Gy) and 7-37% (18 Gy). This GI was greater or equal to that observed with HDR alone. For the HDR group, the addition of PABA resulted in a more moderate increase in GI by 7-46% (6 Gy) and 10-36% (12 Gy). With TMZ alone and no RT, GI rates were 26% (T98G), 75% (U118) and 90% (U87MG). With PABA alone and no RT, GI rates were 57% (T98G), 55% (U118) and 73% (U87MG). The combination of PABA and TMZ with no RT increased GI to 52% only in the TMZ-resistant T98G cells. Conclusions: PABA enhances radiation responses both with LDR and HDR radiation. HDR radiation improves cell killing in all three cell lines. Without RT, PABA alone or in combination with TMZ doubles tumor GI in TMZ-resistant cells. This is the first in-vitro study to demonstrate modulation of radiation responses with LDR and HDR RT and show significant PABA modulation at LDR in glioblastoma cells. Currently, we are combining pre-treatment with PABA and TMZ followed by HDR and LDR RT in these and other glioblastoma cell lines. p21 and key signaling pathways are being examined by Western Blot, and apoptotic responses are being assessed. With the clinical availability of Tomotherapy, it becomes relevant to further study the mechanism of action of this combined therapy and assess the role of PABA as potential adjuvant to RT in malignant brain tumors. Supported in part by The Chemotherapy Foundation and Cancer Innovations, Inc.
PubMed, Nov 15, 1993
Cachexia and malnutrition play a significant role in the morbidity associated with antineoplastic... more Cachexia and malnutrition play a significant role in the morbidity associated with antineoplastic chemotherapy regimens. Conventional nutritional support during cancer therapy has shown little benefit in terms of reducing morbidity and mortality. We examined the anabolic properties of growth hormone (GH) that preserve normal body composition in sarcoma-bearing animals treated with doxorubicin. On day 0, 40 male Fischer 344 rats were inoculated with 10(6) methylcholanthrene-induced sarcoma cells s.c. in the left flank. On day 9, animals were randomized into 3 groups: control (CTL, n = 13); doxorubicin (DOX, n = 13); and doxorubicin plus GH (DOX-GH, n = 14). Two CTL animals were excluded due to tumor invasion into the peritoneal cavity. From day 9 to day 23, the DOX-GH group received daily s.c. recombinant rat GH injection (1 mg/kg). On day 13, DOX and DOX-GH groups received 7 mg/kg of DOX i.v. while the CTL group received sham i.v. sterile saline injection. Body weight and tumor dimensions were measured daily. On day 23, all animals were weighed and sacrificed. Tumors were resected and weighed. Body composition analysis was performed. Plasma GH levels were measured by radioimmunoassay and insulin growth factor 1 levels were measured by chondrocyte proliferation bioassay. The DOX-GH group had a significantly higher mean body weight, carcass weight, total fat free body mass, insulin growth factor 1, and GH plasma levels as compared to the DOX group. No difference in total food intake was observed between the DOX and DOX-GH groups. There was no difference in final tumor weight and tumor growth rate between DOX and DOX-GH groups. Exogenous growth hormone can attenuate weight loss and preserve host body composition in tumor-bearing rats treated with doxorubicin without stimulating tumor growth.
The Annals of Thoracic Surgery, Sep 1, 1995
Background. Isolated single-lung perfusion with doxorubicin hydrochloride was shown to be effecti... more Background. Isolated single-lung perfusion with doxorubicin hydrochloride was shown to be effective in clearing experimental sarcoma lung metastases in the rat. The best perfusate to be used for isolated lung perfusion and factors affecting the final lung concentration of doxorubicin are the subject of the present study. In experiment 1, 60 animals were randomized to undergo isolated left lung perfusion with doxorubicin with six different perfusates (n = 10 per group): saline, low-potassium-dextran, 5% albumin, 6% hetastarch, 5~/, buffered albumin, and 6% buffered hetastarch. Five animals served as negative controls. After perfusion, the lung wet to dry ratio and final lung doxorubicin concentration were determined. In experiment 2, 60 animals underwent isolated left lung perfusion with either 80 /~g/mL or 320 /~g/mL of doxorubicin. Animals were perfused at either 0.5 mL/min or 1 mL/min and for 2, 6, or 10 minutes. At the end of the perfusion period, the left lung doxorubicin concentration was measured. Statistical analysis included analysis of variance, the Duncan test for multiple comparisons, and multiple linear regression analysis. Significance was defined as a p value of less than 0.05.
PubMed, Aug 1, 2002
Treatment with the proteasome inhibitor, PS-341 resulted in concentration- and time-dependent eff... more Treatment with the proteasome inhibitor, PS-341 resulted in concentration- and time-dependent effects on Bcl-2 phosphorylation and cleavage in H460 cells that coincided with the PS-341-induced G2-M phase arrest. The observed Bcl-2 cleavage paralleled the degree of PS-341-induced apoptosis but was detected to a similar extent with comparable concentrations of two other proteasome inhibitors (MG-132 and PSI). Calpain inhibitors, ALLM and ALLN, and the caspase inhibitors, Z-VAD and AC-YVAD did not induce BcI-2 phosphorylation and cleavage. Exposure to PS-341 resulted in an additional Mr 25,000 cleavage fragment of Bcl-2, whereas only a Mr 23,000 fragment was observed with other anticancer agents. The formation of the Mr 25,000 fragment was not prevented by caspase inhibitors unlike the Mr 23,000 fragment, which suggests mediation by a caspase-independent pathway. Cell fractionation studies revealed that the Bcl-2 cleaved fragments localize within membrane structures and was an early event (at approximately 12 h, posttreatment), and before the observed cleavage of poly(ADP-ribose) polymerase (PARP), beta-catenin, and DNA fragmentation (at approximately 36 h posttreatment). The Mr 23,000 Bcl-2 cleavage product was inhibited by the pan-caspase inhibitor and the inhibitors of capase-3, -8, -9; but the PARP cleavage was prevented only by the pan-caspase and caspase-3 inhibitors, which suggests that the Mr 23,000 Bcl-2 cleavage occurred at both the initiation and execution stages of apoptosis. The inhibition of the ubiquitin/proteasome pathway by PS-341 leads, at an early stage of apoptosis, to Bcl-2 phosphorylation and a unique proteolytic cleavage product, which are associated with G2-M phase arrest and the induction of apoptosis.
International Journal of Radiation Oncology Biology Physics, Mar 1, 2004
Ionizing radiation can reduce tumor growth outside the field of radiation, known as the abscopal ... more Ionizing radiation can reduce tumor growth outside the field of radiation, known as the abscopal effect. Although it has been reported in multiple malignancies, the abscopal effect remains a rare and poorly understood event. Ionizing radiation generates inflammatory signals and, in principle, could provide both tumor-specific antigens from dying cells and maturation stimuli that are necessary for dendritic cells' activation of tumorspecific T cells. We therefore tested the hypothesis that the abscopal effect elicited by radiation is immune mediated. This was directly tested by enhancing the number of available dendritic cells using the growth factor Flt3-Ligand (Flt3-L). Methods and Materials: Mice bearing a syngeneic mammary carcinoma, 67NR, in both flanks were treated with Flt3-L daily for 10 days after local radiation therapy (RT) to only 1 of the 2 tumors at a single dose of 2 or 6 Gy. The second nonirradiated tumor was used as indicator of the abscopal effect. Data were analyzed using repeated measures regression. Results: RT alone led to growth delay exclusively of the irradiated 67NR tumor, as expected. Surprisingly, growth of the nonirradiated tumor was also impaired by the combination of RT and Flt3-L. As control, Flt3-L had no effect without RT. Importantly, the abscopal effect was shown to be tumor specific, because growth of a nonirradiated A20 lymphoma in the same mice containing a treated 67NR tumor was not affected. Moreover, no growth delay of nonirradiated 67NR tumors was observed when T cell deficient (nude) mice were treated with RT plus Flt3-L. Conclusions: These results demonstrate that the abscopal effect is in part immune mediated and that T cells are required to mediate distant tumor inhibition induced by radiation.
Clinical Cancer Research, Sep 30, 2008
Purpose: Extracellular matrix remodeling during tumor growth plays an important role in angiogene... more Purpose: Extracellular matrix remodeling during tumor growth plays an important role in angiogenesis. Our preclinical data suggest that a newly identified cryptic epitope (HU177) within collagen type IV regulates endothelial and melanoma cell adhesion in vitro and angiogenesis in vivo. In this study, we investigated the clinical relevance of HUI77 shedding in melanoma patient sera. Experimental Design: Serum samples from 291 melanoma patients prospectively enrolled at the New York University Medical Center and 106 control subjects were analyzed for HU177 epitope concentration by a newly developed sandwich ELISA assay. HU177 serum levels were then correlated with clinical and pathologic parameters. Results: Mean HU177 epitope concentration was 5.8 ng/mL (range, 0-139.8 ng/mL). A significant correlation was observed between HU177 concentration and nodular melanoma histologic subtype [nodular, 10.3 F 1.6 ng/mL (mean F SE); superficial spreading melanoma, 4.5 F 1.1ng/mL; all others, 6.1 F2.1ng/mL; P = 0.01byANOVA test]. Increased HU177 shedding also correlated with tumor thickness (V1.00 mm, 3.8 F 1.1 ng/mL ; 1.01-3.99 mm, 8.7 F 1.3 ng/mL; z4.00 mm, 10.3 F 2.4 ng/mL; P = 0.003 by ANOVA). After multivariate analysis controlling for thickness, the correlation between higher HU177 concentration and nodular subtype remained significant (P = 0.03). The mean HU177 epitope concentration in control subjects was 2.4 ng/mL. Conclusions: We report that primary melanoma can induce detectable changes in systemic levels of cryptic epitope shedding. Our data also support that nodular melanoma might be biologically distinct compared with superficial spreading type melanoma. As targeted interventions against cryptic collagen epitopes are currently undergoing phase I clinical trial testing, these findings indicate that patients with nodular melanoma may be more susceptible to such targeted therapies.
Correlation of shedding cryptic epitope (HU177) levels and treatment response in sera of melanoma patients
Journal of Clinical Oncology, May 20, 2008
20018 Background: We have previously shown that shedding of the recently identified cryptic epito... more 20018 Background: We have previously shown that shedding of the recently identified cryptic epitope HU177 can be measured in melanoma patients’ sera and correlates with invasiveness of primary melanomas. Here we prospectively measured HU177 collagen epitope (HCE) titers in sera of stage IV melanoma patients (pts) enrolled in two clinical trials conducted at our institution. Methods: Serum samples from 37 pts (11-M1a, 10-M1bM, 16-M1c) who received Sorafenib on an NCI phase II trial (6617) (study A) and from 18 stage IV pts who were treated 2nd line with Carboplatin, Paclitaxel, and PABA on a phase I trial (study B), were analyzed for HCE by a dual sandwich ELISA during each of up to 12 cycles. Serum was aliquoted into 200 μl volumes and stored at - 20°C until assayed. Correlation of HCE levels with treatment response as measured by PET/CT or CT imaging was examined. Results: In 2 of 3 radiographically responding pts in study A correlation with HCE was seen. In one pt, HCE levels dropped from 74.4 ng/ml to ...
Bortezomib with Taxanes
Humana Press eBooks, 2004
We have examined the use of combinations of bortezomib (PS-341) with docetaxel in in vitro and in... more We have examined the use of combinations of bortezomib (PS-341) with docetaxel in in vitro and in vivo studies and have added the use of localized delivery of radiation in in vitro combinations through the use of a 90Y-labeled monoclonal antibody, BrE-3. In in vitro studies, marked cytotoxic effects from the combination of PS-341/docetaxel were seen progressively with the ovarian cell line SKOV3 over the time period of 24–72 h, with additive activity at 48 h and synergistic activity at 72 h. In non-small cell lung cancer (H460 cell) PS-341 induced a 25-kDa Bcl-2 cleavage product different from fragments produced by other anticancer agents. This unique Bcl-2 cleavage product was an early event starting 12 h after PS-341 exposure, followed by DNA fragmentation and cleavage of caspase-mediated PARP and β-catenin at 36 h. Results with ovarian xenograft model showed the beneficial effects of combined treatment with PS-341 and docetaxel: tumor growth was limited for a 30-d period following the cessation of treatment compared with single agents alone. Significant augmentation of cytotoxicity at and below therapeutic levels of PS-341 and docetaxel were observed with radioimmunotherapy studies using ovarian and breast cancer cell lines.
Systemic anti-cancer effects are triggered by local treatment with ionizing radiation and FLT3-Ligand in a syngeneic mouse model of mammary carcinoma
International Journal of Radiation Oncology Biology Physics, Oct 1, 2002
Para-aminobenzoic acid (PABA) enhances the in-vitro tumor response of ovarian cancer to Topotecan (TTN) through mitochondrial-mediated apoptosis
Cancer Research, May 1, 2005
Molecular Therapy, 2011
Jak Inhibitors Mitigate Lipid-siRNA Toxicities lysate assay (Lonza, Basel, Switzerland). In all L... more Jak Inhibitors Mitigate Lipid-siRNA Toxicities lysate assay (Lonza, Basel, Switzerland). In all LNP-siRNA preparations used in our animal studies, the endotoxin levels at the highest dose of LNP05-siRNA were <0.25 EU/kg (body weight), significantly below the endotoxin release limit for humans (5 EU/kg), defined by US Food and Drug Administration and World Health Organization.
A simplified method for endotracheal intubation in the rat
Journal of Applied Physiology, Apr 1, 1994
Endotracheal intubation in small laboratory animals is often necessary for survival experiments. ... more Endotracheal intubation in small laboratory animals is often necessary for survival experiments. Methods of airway control have included tracheostomy, blind intubation, and intubation under direct vision. Most of these methods are unsatisfactory and associated with high failure and complication rate. We developed an easy method of endotracheal intubation in the rat that requires simple material that is easily available to any research facility. The animals were anesthetized with pentobarbital sodium, the tongue was pulled out, and an otoscope was introduced into the oropharynx. By direct vision, a guide wire was inserted into the trachea and a 16-gauge intravenous catheter was glided over the wire. The first group of 70 rats underwent left thoracotomy with endotracheal intubation and mechanical ventilation at our laboratory as part of a study on isolated lung perfusion. The second group of five rats was anesthetized with pentobarbital, and a left carotid catheter and an endotracheal tube were inserted. Animals were ventilated with 100% O2. Arterial blood gases were sampled before intubation, 30 min after ventilation, and 60 min after extubation. In the first group, 94.3% (66 of 70) of the animals survived surgery and mortality was not directly related to the intubation and/or ventilation. All five animals of the second group survived the procedure to be extubated. Arterial PO2 before intubation, 30 min after intubation and ventilation, and 60 min after extubation was 77.1 +/- 8.5, 465.0 +/- 55.6, and 98.9 +/- 12.8 Torr, respectively. PCO2 at the same time points was 42.5 +/- 10.1, 35.1 +/- 6.3, and 32.7 +/- 6.5 Torr, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
The Annals of Thoracic Surgery, Aug 1, 1993
Unilateral pulmonary artery occlusion inhibits growth of metastatic sarcoma in the rat lung
Journal of Surgical Oncology, Nov 1, 1994
Tumors depend on their blood supply for growth. The blood supply to metastatic neoplasia of lung ... more Tumors depend on their blood supply for growth. The blood supply to metastatic neoplasia of lung is usually from the pulmonary circulation or both the pulmonary and systemic circulation. The antineoplastic effect of pulmonary artery occlusion was investigated in a rat model of methylcholanthrene‐induced metastatic pulmonary sarcoma. Left pulmonary artery ligation was performed on day 7 after tumor inoculation, and animals were sacrificed on day 14. The tumor burden of the left lung decreased 44% when compared with the control group. The survival of non‐tumor‐bearing rats undergoing left pulmonary artery ligation for 24 hours followed by right pneumonectomy after 2 weeks was also studied. No significant lung damage after a period of left pulmonary artery ligation was seen, as evidenced by both survival after contralateral right pneumonectomy and histology. Balloon occlusion of pulmonary artery, together with regional chemotherapy for patients with lung metastases, may warrant investigation. © 1994 Wiley‐Liss, Inc.
Establishment of an Experimental Intrapulmonary Tumor Nodule Model
The Annals of Thoracic Surgery, Jul 1, 1997
A pulmonary tumor model is necessary to study the biology and therapy of lung cancer. Methods to ... more A pulmonary tumor model is necessary to study the biology and therapy of lung cancer. Methods to establish a solitary intrapulmonary nodule are not well defined. Two methods for solitary intrapulmonary tumor nodule development in the Fischer rat are described. Methylcholanthrene-induced sarcoma cell suspensions were introduced into lung parenchyma of Fischer rats via limited thoracotomy and lung puncture, or instilled into a distal airway after tracheal puncture and catheterization. Intrapulmonary tumor location, implantation mortality, procedure length, and animal survival were recorded. Single pulmonary nodules developed at the implanted position in 100% (n = 320) and 95% (62/65) of animals after direct injection into the pulmonary parenchyma or via tracheal puncture and instillation. Operative mortality was 2% and 5% via lung or tracheal implantation, respectively. Less than 5 minutes was required for each implantation. Mean survival time was 24 +/- 2 and 26 +/- 6 days after lung or tracheal implantation in animals allowed to survive until tumor-induced death. These easily performed, reproducible methods of establishing solitary intrapulmonary tumors are useful tools for lung cancer research.
Specific organ gene transfer in vivo by regional organ perfusion with herpes viral amplicon vectors: Implications for local gene therapy
Surgery, Mar 1, 2001
Many gene therapy strategies would benefit from efficient, regional organ delivery of therapeutic... more Many gene therapy strategies would benefit from efficient, regional organ delivery of therapeutic genes. Regional perfusions of lung, liver, or bladder were performed to determine if rapid and efficient gene transfer can be accomplished in vivo, and to determine if in vivo gene transfer can be limited to the organ of interest. In addition, herpes simplex virus tumor necrosis factor (HSVtnf), carrying the human tumor necrosis factoralpha gene was used as a treatment for methylcholanthrene sarcoma in a syngeneic lung metastases model in Fisher rats. A 20-minute perfusion using HSV carrying beta-galactosidase (HSVlac) produced significant expression of this marker gene isolated to the target organs, without organ-specific tissue injury or inflammation. Regional perfusion of organs with HSV carrying the cytokine gene tumor necrosis factor alpha also resulted in high-level local organ production of this cytokine (2851 +/- 53 pg/g tissue in perfused lung versus 0 for the contralateral lung). For the current vector construct, expression of the gene of interest peaked between 2 and 4 days and was undetectable by 2 weeks after perfusion. In animals undergoing perfusion as treatment for pulmonary sarcoma, there was no difference between tumor counts in lungs perfused with HSVlac (17 +/- 6) or HSVtnf (22 +/- 8), but either treatment resulted in lower tumor counts than controls (111 +/- 24 nodules per lung, P <.02). Regional organ perfusion using herpes viral vectors is an effective and well-tolerated in vivo method of transiently delivering potentially toxic gene products to target organs in directing gene therapy. Regional lung perfusion with HSV amplicons reduces tumor burden in a rat model of pulmonary metastases, though HSVtnf cannot be demonstrated to augment the cytopathic effect of the HSV amplicon alone in the current model.
Annals of Surgical Oncology, Jul 1, 1994
Background: The relative effects of growth hormone on tumor versus host growth and protein metabo... more Background: The relative effects of growth hormone on tumor versus host growth and protein metabolism are not known. This study examines the influence of recombinant rat growth hormone (r-rGH) on host and tumor growth, host body composition, and protein synthesis of tumor and host in tumorbearing rats. Methods: After left flank implantation of methylcholanthrene-induced sarcoma, 28 Fischer rats with palpable tumor were treated with s.c. saline or 1 mg/kg/day r-rGH for 11 days. At death, fractional protein synthetic rates (FSRs) of tumor, liver, and gastrocnemius muscle were determined. In a separate experiment, 27 tumor-bearing rats received saline or 1 mg/kg/day r-rGH for 2 weeks. Tumor and host growth and host body composition were analyzed. Results: Animals treated with r-rGH had significantly higher liver FSR than did controls (233-+ 27%/day vs. 110-+ 4%/day, respectively). No significant differences were associated with growth hormone administration with respect to tumor growth, host composition, or FSR of tumor or muscle. Conclusions: Growth hormone stimulates liver protein synthesis, without changing tumor growth, protein synthesis, or host composition in this rat sarcoma model. Further investigation of growth hormone as an anticachectic agent is warranted.