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PubMed1995

Increased tumor oxygenation and radiation sensitivity in two rat tumors by a hemoglobin-based, oxygen-carrying preparation.

The rat 13762 mammary carcinoma and the rat 9L gliosarcoma were grown subcutaneously in a hind limb of female, Fisher 344 rats. The oxygen content of the tumors was determined using an Eppendorf pO2 histograph. Fifty-to-sixty oxygen measurements were made per tumor and there were 8-to-10 animals per group. The percent of pO2 readings < or = 5 mmHg in the mammary carcinoma was 49%, this was decreased to 34% by administration of the hemoglobin preparation (8 ml/kg) and further decreased to 29% when carbogen (95% O2/5% CO2) breathing was added to administration of the hemoglobin preparation. The percent of pO2 readings < or = 5 mmHg in the gliosarcoma was 49%, this was decreased to 24% by administration of the hemoglobin preparation and further decreased to 0% when carbogen breathing was added to administration of the hemoglobin preparation. Therapeutic response was assessed over a single-dose range of radiation therapy (10, 20 and 30 Gray). The dose modifying factor produced by the hemoglobin preparation/air was 1.6 and by the hemoglobin preparation/carbogen was 2.7 in the rat 13762 mammary carcinoma. The dose modifying factor produced by the hemoglobin preparation/air was 1.9 and by the hemoglobin preparation/carbogen was 2.9 in the rat 9L gliosarcoma. Administration of a hemoglobin-based oxygen carrier reduced tumor hypoxia and increased tumor response to radiation therapy.

Adenocarcinoma↗
PubMed1985

Immunohistochemical study of glial fibrillary acidic protein in avian sarcoma virus-induced gliomas in dogs.

Anaplastic astrocytomas, gliosarcomas and sarcomas were induced in 33 neonatal dogs by intracerebral injection of purified Schmidt-Ruppin strain of avian sarcoma virus (ASV). A total of 11 anaplastic gliomas, 7 gliosarcomas and 18 sarcomas were induced. Ten of the 11 anaplastic astrocytomas and all 7 gliosarcomas were positive for GFAP using the peroxidase-antiperoxidase method on formalin-fixed, paraffin embedded tissue. None of the sarcomas were positive for GFAP. One anaplastic astrocytoma was analyzed by gel electrophoresis and immunoblot and the amount of GFAP in the tumor was compared with comparable samples from normal white and gray matter. Densitometric analysis of the GFAP stained gels showed that 12-13% of tumor protein was GFAP compared with 2-3% for the non-neoplastic white and gray matter. The results of this study add further evidence to the astrocytic origin of many of the induced anaplastic primary brain tumors by ASV.

Animals↗
PubMed2001

Characterisation of molecular alterations in microdissected archival gliomas.

Classification of gliomas according to their molecular characteristics may be important in future histopathological diagnosis. However, gliomas frequently display heterogeneity at the histological, biological and molecular level. In this study of archival diagnostic gliomas, precision microdissection was used to enrich samples in the most malignant cells or to investigate intratumoural histological heterogeneity. Analysis of tumour samples microdissected from the most aggressive regions, representative of the histopathological diagnosis, revealed PTEN mutations in 4/14 anaplastic astrocytomas, 4/13 glioblastomas and 1 gliosarcoma, but not in 19 low-grade gliomas. Using a novel PCR procedure and direct sequence analysis of the entire coding sequence, TP53 mutations were detected in 1/3 pilocytic astrocytomas, 3/13 astrocytomas, 4/14 anaplastic astrocytomas, 5/13 glioblastomas and 1 gliosarcoma. All but one of the tumours with TP53 mutation showed p53 immunopositivity, but 5 low-grade and 10 high-grade gliomas had p53 protein nuclear accumulation in the absence of detectable mutation. p53 status was unrelated to p21 expression. Neither PTEN nor TP53 mutations influenced the proliferative index or microvessel density of high-grade astrocytomas. Unusual findings include: TP53 mutation in a juvenile pilocytic astrocytoma; TP53 and PTEN mutations in a de novo glioblastoma, a gliosarcoma with identical mutations in gliomatous and sarcomatous components, and an infratentorial anaplastic astrocytoma with an earlier supratentorial grade II astrocytoma bearing the same TP53 mutation but not the PTEN mutation or loss of heterozygosity (LOH) of 10q23. Similarly, the transition to high-grade histology was associated with acquisition of PTEN mutations and 10q23.3 LOH in two de novo high-grade tumours with regions of low-grade histology.

Adolescent↗
PubMed1999

Connexins are expressed in primary brain tumors and enhance the bystander effect in gene therapy.

OBJECTIVE: Experimental brain tumor gene therapy with the herpes simplex virus thymidine kinase (HSV-tk) gene has demonstrated that not only HSV-tk transduced but surrounding non-HSV-tk transduced cells are killed when given ganciclovir. This so-called bystander effect has recently been shown to be dependent on connexin-mediated intercellular communication. To assess potential susceptibility to the bystander effect, we examined levels of connexin-26 and connexin-43 expression in a series of primary brain tumors. Connexin-26 expression has not previously been studied in primary brain tumors and connexin-43 expression has not been studied in nonastrocytic primary brain tumors. We also attempted to enhance the bystander effect in vitro by overexpressing connexin in tumor cells with high basal levels of connexin expression. METHODS: Western blot analysis and immunohistochemistry were used to determine levels of connexin-26 and connexin-43 expression in a series of primary brain tumors. Wild-type 9L gliosarcoma cells were transfected in vitro with the connexin-43 gene and the HSV-tk gene or the HSV-tk gene alone. The bystander effect of each transfectant was then assessed and compared. RESULTS: Most of the primary brain tumors tested, including low-grade astrocytomas, anaplastic astrocytomas, glioblastomas, oligodendrogliomas, gangliogliomas, meningiomas, and medulloblastomas, showed connexin-26 and connexin-43 expression. Bystander experiments revealed a significant enhancement of the bystander effect in the gliosarcoma cells transfected with connexin-43 and HSV-tk, as compared with gliosarcoma cells transfected with HSV-tk alone. CONCLUSION: Most primary brain tumors express connexin-26 and connexin-43. This suggests that most primary brain tumors may be susceptible to the bystander effect of HSV-tk gene therapy. The bystander effect can be enhanced in vitro by overexpression of connexin-43 in a cell line with a high basal level of connexin-43 expression.

Animals↗
PubMed2005

Local delivery of a synthetic endostatin fragment for the treatment of experimental gliomas.

OBJECTIVE: Endostatin is an anti-angiogenic agent that blocks matrix-metalloproteinase-2 and inhibits endothelial cell proliferation. Currently, endostatin is available through recombinant technology, which limits its broader use. In this study, a synthetic endostatin fragment (EF) was analyzed to determine its anti-angiogenic properties when locally delivered by controlled-release polymers and to establish its effect as a treatment for experimental gliomas. METHODS: Cytotoxicity of EF against 9L gliosarcoma and F98 glioma was determined in vitro. EF was loaded into polyanhydride-poly-(bis-[carboxyphenoxy-propane]-sebacic-acid) (pCPP:SA) polymers at increasing concentrations. Pharmacokinetics of the EF/polymer formulations were defined in vitro. Anti-angiogenic properties of the EF/polymer formulations were evaluated in the rat-cornea micropocket assay. Toxicity and efficacy of locally delivered EF polymers either alone or combined with systemic bischloroethylnitrosourea (carmustine) were determined in rats intracranially challenged with 9L gliosarcoma. RESULTS: EF showed scarce cytotoxicity against 9L and F98 in vitro. EF/pCPP:SA formulations showed sustained release by day 19. Mean corneal angiogenesis index 20 days after tumor implantation was 4.5 +/- 0.7 for corneas implanted with 40% EF/pCPP:SA compared with controls (8.5 +/- 1.3, P = 0.02). Intracranial efficacy studies showed that EF polymers alone did not prolong animal survival. Combination of 40% EF/pCPP:SA polymers with systemic bischloroethylnitrosourea (carmustine) prolonged survival (median survival of 44 d, P = 0.001) and generated 33% long-term survivors. CONCLUSION: Controlled-release polymers can effectively deliver a biologically active EF in a sustained fashion. EF inhibits angiogenesis in vitro and in vivo, and even though EF does not prolong survival as a single agent, it exhibits a synergistic effect when combined with systemic bischloroethylnitrosourea (carmustine) in the intracranial 9L gliosarcoma model.

Animals↗
PubMed2003

Determination of RNA expression for cholecystokinin/gastrin receptors (CCKA, CCKB and CCKC) in human tumors of the central and peripheral nervous system.

Gastrin (G17) belongs to the cholecystokinin (CCK) peptide family widely distributed in the brain, and we were the first to show that it significantly modulates the growth and migration features of tumor astyrocytes. Conflictual data have been published as to whether CCKA, CCKB and CCKC receptors are, or are not, present in tumors of the central and peripheral nervous system (CPNS) in general, and in gliomas in particular. In the present study we employed polymerase chain reaction (PCR) on a series of 29 CNPS tumors, including 20 gliomas (17 astrocytic and 3 oligodendroglial tumors), 4 schwannomas and 5 meningiomas to investigate whether RNAs were present or absent in the case of these CCKA, CCKB and CCKC receptors. The presence of the three CCK receptor subtypes was also assayed on three experimental models, i.e. the U373 human glioma, the C6 rat glioma and the 9L rat gliosarcoma. The data show that 9/20 (45%) of the gliomas exhibited RNAs for the CCKB receptor as did the C6 rat glioma, 13/20 (65%) RNAs for the CCKC receptor as did the U373 human glioma and the 9L rat gliosarcoma. Of the 20 gliomas, 17 (85%) expressed RNAs for either the CCKB or the CCKC receptor (or both), a feature which was also observed in the experimental models. One schwannoma and one meningioma exhibited RNAs for the CCKB receptor, while 4/4 schwannomas and 4/5 meningiomas showed RNAs for the CCKC receptor. None of the gliomas, schwannomas or meningiomas exhibited RNAs for the CCKA receptor, which were found in the 9L rat gliosarcoma model only. These data emphasize that 85% of the gliomas under study and 86% (25/29) of the tumors of the central and peripheral nervous system exhibited CCKB and/or CCKC receptors. This therefore suggests an important role for gastrin in the biological development of these tumors.

Animals↗
PubMed1992

[Angiogenesis induced by rat glioma cells in vitro].

Angiogenesis induced by rat glioma cells was examined in vitro using a double chamber co-culture system. Cultured microvascular endothelial cells from Fisher 344 rat brain, rat C6 glioma cells and rat T9 gliosarcoma cells were used for this study. Endothelial cells, cultured on type I collagen, formed capillary-like structures. In the co-culture system, C6 glioma cells promoted this formation. On the other hand T9 gliosarcoma cells had no effect on it. The supernatants of C6 glioma cells and T9 gliosarcoma cells suppressed the proliferation of the endothelial cells. C6 glioma cells probably produce and release soluble factors promoting angiogenesis. The proliferation of endothelial cells is thus suppressed while angiogenesis is made more intense. This in-vitro model is useful to elucidate the mechanism of tumor angiogenesis and to evaluate the promoting and inhibiting factors of angiogenesis.

Angiogenesis Inducing Agents↗
PubMedDate not supplied

Effects of free and liposome-encapsulated taxol on two brain tumors xenografted into nude mice.

Free taxol and liposome-encapsulated taxol were compared for their antitumoral activities on two human brain tumors serially grafted into female athymic mice in the scapular region. In the first experiment, a human glioblastoma (15th and 16th passages) was studied. In the second experiment, a fast growing human gliosarcoma (19th passage) was used. Free taxol and liposomal taxol were administered intraperitoneally, at the same dose; 12.5 mg/kg (i.e. 1/15 of the evaluated LD 50 value). In the first experiment, the treatment was performed for four consecutive days, with four courses separated by three rest periods of three days in between. Both free taxol and encapsulated taxol produced a statistically significant delay in tumor growth, and at the end of the experiment some total tumor regressions were obtained. However, liposomes were observed to be more effective in their action on the two consecutive passages of the glioblastoma, giving a marked increase of the number of total tumor regressions. In the second experiment another schedule of treatment was chosen because of the fast growth pattern of the xenografted human gliosarcoma: free taxol and liposome-encapsulated taxol were administered for five consecutive days and three courses of treatment were performed with two rest periods of two days. The two forms of taxol had a significant inhibitory effect on gliosarcoma tumor growth; as before encapsulation in liposomes was found to increase the anti-tumoral activity of taxol, although, in this case no tumor regression was observed.

Alkaloids↗
PubMed2004

The concentration of thyroid hormones and activities of iodothyronine deiodinases are altered in human brain gliomas.

We have determined the cellular concentration of thyroxine (T4) and triiodothyronine (T3) and the activities of two brain iodothyronine deiodinases, type II (5'-D2) and type III (5-D3), in two types of tissues --tumour (26) and non-tumour (5), derived either from human gliomas with various histological malignancies or from non-tumoural surrounding brain tissue. As it has been established, all patients before the surgery had the Non-Thyroidal Illness Syndrome (NTIS). The concentration of serum T3 was therefore significantly decreased in all the examined patients. It was over 2.5 times lower than that before surgery and 4.0 times lower at surgery than that seen in healthy controls. The serum concentration of T4 was found to be below normal range in 4/26 cases and in low levels of normal range in 6/26 cases, whereas TSH serum concentration in all patients was within normal range. The concentrations of T3 and T4 (expressed as pg of hormone/mg tissues protein) in 22/26 brain tissue samples were significantly lower in gliomas than in 5 non-tumoural brain tissue samples. As expected, the alternation in brain 5'D II activity in gliomas was seen in most cases with astrocytomas (5/8 cases), gliosarcomas (8/8 cases) and glioblastoma multiforme (10/10 cases). In general, the mean enzyme activity in tumour tissue was significantly higher than that found in non-tumoural tissue of human brain (21.79 fmol of newly generated T3/h/mg of protein vs. 4.88 fmol of T3/h/mg protein, respectively). The highest 5'D2 activity with a range from 10.82 to 45.96 (mean 23.61 fmol T3/h/mg protein) was found in gliosarcomas. The activity of 5-D3 was increased (in 8/8 cases of gliosarcoma and in 9/10 cases of glioblastoma multiforme) or decreased (in 3/3 cases of astrocytoma II, 5/5 cases of astrocytoma III) when compared to mean activity of this enzyme found in non-tumoural brain tissue. In summary, our results suggest that the concentration of brain iodothyronines and metabolism of thyroid hormones in the examined human brain tumours are altered. These changes may be related to malignant progression.

Adult↗
PubMed1987

Ploidy of endothelium in high-grade astrocytomas.

To determine the ploidy and proliferative activity of the endothelium in high-grade astrocytomas, the nuclear DNA content of 11 high-grade astrocytomas, including two gliosarcomas, was measured by cytophotometry. This technique allowed comparison of the endothelial population with the astrocytic population. In all cases, the endothelium was diploid, with an average of 24.6% of cells in the S + G2M phases of the cell cycle. In contrast, the astrocytic population displayed marked DNA abnormalities. The two gliosarcomas had a marked difference in proliferative activity of the endothelium with 4% and 40% of cells, respectively, in the S + G2M phases. These data indicate that the vast majority of endothelial cells compromising the vascular hypercellularity observed in high-grade astrocytomas are in the normal cell cycle whereas in many cases the malignant astrocytes are not. The nuclear DNA content of gliosarcomas appears to be similar to other high-grade astrocytomas.

Cell Division↗
PubMedDate not supplied

Purified herpes simplex thymidine kinase Retrovector particles. I. In vitro characterization, in situ transduction efficiency, and histopathological analyses of gene therapy-treated brain tumors.

Replication-defective, highly purified retroviral vectors (Retrovector), at titers of 10(8) colony forming units/mL, were prepared that conferred either beta-galactosidase or herpes simplex thymidine kinase (HSV-TK) activity. 9L gliosarcoma cells, transduced efficiently in vitro, were highly sensitive to ganciclovir (GCV). The mean frequency of in situ transduction, measured by flow cytometry of single-cell tumor suspensions isolated from rat brains, was 3.2 +/- 0.6%; similar assessments were made by staining of beta-galactosidase or by immunohistochemistry with anti-HSV-TK. In vitro HSV-TK-transduced and G418-selected 9L-TK gliosarcoma tumors treated with GCV were eradicated in approximately 53% of the animals (10/19) at day 26, however, 89% (17/19) histologically showed < 1% tumor volume. Histologic evaluation at day 26 of animals with established 9L tumors treated with intralesional injection of HSV-TK vector followed by GCV treatment showed that 29% (4/14) had no tumor; 50% (7/14) had < 1% tumor volume. Regression of tumors proceeded over the time since the complete rate was increased at day 60. Neither HSV-TK vector particles nor GCV alone altered the histological profile of 9L tumors, but substantial numbers of CD4+ and CD8+ lymphocytes infiltrated the tumors of animals treated with both. In cured animals, the former tumor bed contained cell debris, immune cells, and fibroblasts and was without damage to adjacent brain. The efficacy of suicide gene therapy for rat gliosarcoma using highly purified virion vectors approaches that of packaging cell lines.

Animals↗
PubMed1997

Intralesionally implanted cisplatin cures primary brain tumor in rats.

BACKGROUND AND OBJECTIVES: Chemotherapy has added little to the overall survival of the patients with primary malignant brain tumors, primarily due to its difficulty penetrating the blood-brain barrier. Use of polymers, releasing high doses of chemotherapy locally over time, is a promising new treatment strategy. Three experiments were conducted to test the effect of cisplatin, released from biodegradable polymer, on rats with 1 week established brain tumor. METHODS: 9L gliosarcoma cells and drug-free or cisplatin-loaded polymer were administered through a right frontal lobe cannula in male Fischer 344 rats. Tumor cells were infused on day 0 and polymer on day 7. Animals were monitored for 60 days. RESULTS: In experiment one, 0.5 mg/m2 of cisplatin loaded in polymer resulted in a mean survival time (MST) of 51 +/- 14 days with 63% (10/16) rats surviving to day 60. MST for the control group was 24 +/- 4 days (p = 2.5 x 10(-9)). Evidence of clinical or histologic brain toxicity was minimal. In a second experiment, using drug-free polymer (n = 7), MST was 24 +/- 3 days. This was compared against an MST of 24 +/- 4 days in the tumor control group (n = 7) and 49 +/- 7 days in a cisplatin-polymer treated group (n = 6). In a third experiment, two doses of drug-free polymer and three doses of cisplatin-loaded polymer were tested in normal nontumor-bearing rats and found to be well tolerated. CONCLUSIONS: Intralesional sustained release of cisplatin from biodegradable polymer is safe and effective for the treatment of brain 9L gliosarcoma in rats.

Animals↗
PubMed1998

Intralesionally implanted cisplatin plus systemic carmustine for the treatment of brain tumor in rats.

BACKGROUND AND OBJECTIVES: The benefit of conventional chemotherapy for the treatment of malignant brain tumors, although limited, is real. A major obstacle in the treatment of these lesions is the ability to deliver drug across the blood-brain barrier (BBB). Local drug implantation, circumventing the BBB, has been a useful strategy for treatment of intracranial lesions, and may work synergistically with systemic chemotherapy. To test this hypothesis, either intraperitoneal (i.p.) carmustine or cisplatin was combined with the intracranial (i.c.) administration of polymer-delivered cisplatin in rats with intracranial tumors. METHODS AND RESULTS: 9L gliosarcoma tumor cells (5 x 10(3)) were administered through a right frontal lobe cannula in rats 7 days prior to treatments. Cisplatin-loaded biodegradable polymer was then administered via the cannula, with free cisplatin or carmustine injected i.p. Animals were monitored for 60 days post-treatment. In experiment 1, i.c. cisplatin at a dose of 0.5, 1.0, 2.0, and 4.0 mg/m2 resulted in a mean survival time of 34 +/- 3, 39 +/- 14, 47 +/- 11, and 31 +/- 20 days (MST +/- SD), respectively, compared to 26 +/- 4 days in the control group and 30 +/- 7 days in the group treated with 50 mg/m2 i.p. free cisplatin. In experiment 2, i.p. free cisplatin at 25, 40, 50, and 100 mg/m2 resulted in a MST of 28 +/- 3, 30 +/- 4, 32 +/- 3, and 14 +/- 8 days, respectively, compared to 26 +/- 1 days in the control group. In experiment 3, the MST in the groups treated with 0.5 mg/m2 of i.c. cisplatin, 25 mg/m2 of i.p. cisplatin, 10 mg/kg of i.p. carmustine, i.c. cisplatin (0.5 mg/m2) plus i.p. cisplatin (25 mg/m2), and i.c. cisplatin (0.5 mg/m2) plus i.p. carmustine (10 mg/kg) was 30 +/- 4 days (P > 0.05), 28 +/- 2 (P > 0.05), 36 +/- 4 (P < 0.01), 32 +/- 3 (P < 0.01), and 50 +/- 11 days (P < 0.01), respectively, compared to the tumor control group (26 +/- 1 days). Long-term survivors (29%) were seen only in the i.c. cisplatin plus i.p. carmustine group. Additive toxicity was not observed. CONCLUSIONS: Intralesional polymer-delivered (i.c.) cisplatin plus systemic (i.p.) carmustine is highly effective for the treatment of intracranial 9L gliosarcoma in tumors.

Animals↗
PubMed1997

The effect of ganciclovir on herpes simplex virus-mediated oncolysis.

Entry of herpes simplex virus (HSV) into tumor cells results in viral gene expression followed by cellular lysis. Attenuated HSVs selectively destroy tumors with sparing of surrounding normal tissue. HSV encodes a thymidine kinase (TK) that converts ganciclovir to a toxic metabolite. This metabolite may be transferred between cells and lead to the death of neighboring uninfected cells, termed bystanders. We sought to determine if HSV-mediated oncolysis is enhanced by ganciclovir treatment. In addition, we examined bystander killing in cocultures of TK transfectants and parental cells. hrR3, an attenuated HSV, expresses TK. The 50% lethal dose of hrR3 for a rat gliosarcoma (9L) and three human colorectal carcinomas (HT29, KM12C6, and KM12L4) was determined. Cells were infected with a 50% lethal dose of hrR3, followed by treatment with ganciclovir, and then cell survival was quantitated. In separate experiments 9L and HT29 cells were transfected with TK. Parental cells and TK transfectants were cocultured in various ratios, in the presence of ganciclovir, and cell survival was quantitated. hrR3-mediated oncolysis was enhanced by ganciclovir in the gliosarcoma but not in the three colorectal carcinomas. Cocultures of both 9L and HT29 parental cells with their corresponding TK transfectants demonstrated bystander killing. The mortality of 9L cocultures was 54% greater than that predicted for exclusive killing of transfectants. HT29 mortality was 8% greater than predicted. The ability of ganciclovir to augment hrR3-mediated oncolysis varies significantly between tumor cells lines. The extent of ganciclovir-mediated killing of neighboring nontransduced parental cells similarly varies. Consideration should be given to these factors in the design of gene therapy strategies using HSV vectors as oncolytic agents.

Animals↗
PubMed1995

Interstitial chemotherapy of experimental brain tumors: comparison of intratumoral injection versus polymeric controlled release.

Interstitial chemotherapy with controlled release polymers is a clinical adjunct in the management of malignant gliomas. The need for polymer to release the chemotherapeutic drug rather than simply injecting the drug into the tumor warrants further investigation. Therefore, we compared the effects of direct intralesional injection of carmustine (BCNU) and 4-hydroperoxycyclophosphamide (4HC) into the rat brain tumor bed with those from the same agents delivered via controlled release polymers implanted intracranially. Treatment was initiated on the fifth day after intracranial implantation of 9L gliosarcoma into male rats; two doses of each drug were injected intratumorally, representing either the amount of drug typically released in vivo from polymer during the first 24 h, or the maximal drug loaded on each polymer. Control rats were treated with empty polymers. We found that the median lifespan was extended in the groups of rats treated with intratumoral injection of BCNU (23% and 36% for 1 mg and 2 mg doses), and 271% with BCNU-impregnated polymer. Similar results were found with intratumoral 4HC (21% and 36% for 0.1 mg and 2 mg injection doses), and 121% with 4HC-impregnated polymer. Overall survival after intraneoplastic injections, however, was not statistically significantly different from that of control rats (p > 0.05). Furthermore, improvement in survival was not consistent, and some animals subjected to 4HC injection died early in the course of treatment. Polymeric treatment resulted in statistically significant prolongation of survival, compared to control rats (p < 0.001 for both BCNU and 4HC). We concluded that direct intralesional injection of BCNU and 4HC is less effective than controlled release via polymers for the treatment of 9L gliosarcoma in the rat model.

Animals↗
PubMed1993

Oxygenation of tumors by a hemoglobin solution.

Tumor oxygen tensions were measured using a computer-controlled PO2 microelectrode in two preclinical solid tumor models, the rat 9L gliosarcoma and the rat 13672 mammary carcinoma. Tumor oxygenation profiles were determined under four conditions: (a) during normal air breathing, (b) during carbogen breathing, (c) after intravenous administration of a solution of ultrapurified polymerized bovine hemoglobin with normal air breathing and (d) after intravenous administration of a solution of ultrapurified polymerized bovine hemoglobin with carbogen breathing. Both tumors had severely hypoxic regions under normal air-breathing conditions. Although carbogen breathing increased the oxygenation of the better-oxygenated portions of the tumor, it made no impact on the severely hypoxic tumor regions. Administration of the hemoglobin solution was effective in increasing the oxygenation throughout both tumors under normal air-breathing conditions. The addition of carbogen breathing to administration of the hemoglobin solution eliminated severe hypoxia in the 9L gliosarcoma and markedly reduced the severely hypoxic regions of the 13672 mammary carcinoma. At 24 h after administration of the hemoglobin solution the 13672 mammary carcinoma showed greater hypoxia than before treatment, which was partially corrected with carbogen breathing.

Adenocarcinoma↗
PubMed2006

Randomized, double-blind, placebo-controlled trial of marimastat in glioblastoma multiforme patients following surgery and irradiation.

PURPOSE: Because raised matrix metalloprotease (MMP) levels are associated with glioma invasion and angiogenesis, we tested the efficacy of marimastat (MT) an orally active drug that can reduce MMP levels, in patients with gliomas. PATIENTS AND METHODS: A total of 162 patients with intracranial glioblastoma multiforme or gliosarcomas who had undergone surgery and radiotherapy participated in this multicenter, double-blind, placebo-controlled, parallel group study conducted at 20 institutions. Seventy-nine patients (57 male, 22 female, median age 58 years) were randomized to receive placebo (PB), and 83 patients (51 male, 32 female, median age 57 years) were randomized to receive MT, 10 mg orally twice daily, until tumor progression. RESULTS: This intention-to-treat efficacy analysis showed no statistically significant difference between MT and PB groups with respect to survival (P = 0.38, log rank test). The median survival time from protocol initiation was 37.9 weeks for the PB group and 42.9 weeks for the MT group, with a hazard ratio of 1.16 (95% CI 0.83 to 1.60). There were no statistically significant differences in quality of life between the PB and MT groups, as assessed by the FACT-BR questionnaire. Musculoskeletal toxicities led to dose modification or withdrawal in 20% of MT-treated and 1.2% of PB-treated patients. CONCLUSION: MT does not improve survival in patients with glioblastoma or gliosarcoma following surgery and radiotherapy. Therefore, single-agent MT appears unwarranted; however, MT in combination with cytotoxic chemotherapy may be warranted, as suggested by observations in our study and other studies.

Adult↗
PubMed2005

Enhancement of the stability of BCNU using self-emulsifying drug delivery systems (SEDDS) and in vitro antitumor activity of self-emulsified BCNU-loaded PLGA wafer.

The main purpose of this study was to develop self-emulsifying drug delivery systems (SEDDS) for the improvement of the stability of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) after released from poly (D,L-lactide-co-glycolide) (PLGA) wafer and to evaluate its in vitro antitumor activity against 9L gliosarcoma cells. The in vitro stability test of BCNU was characterized by the BCNU amount in phosphate buffered saline (PBS, pH 7.4) at 37 degrees C. SEDDS increased in vitro half-life of BCNU up to 130 min compared to 45 min of intact BCNU. Self-emulsified (SE) BCNU was fabricated into wafers with flat and smooth surface by compression molding. In vitro release of BCNU from SE BCNU-loaded PLGA wafer was prolonged up to 7 days followed first order release kinetics. Beside, the cytotoxicity of SE BCNU-loaded PLGA wafer against 9L gliosarcoma cells was higher than intact BCNU-loaded PLGA wafer which is more susceptible to hydrolysis. SE BCNU degraded much more slowly than the intact BCNU in PLGA matrix at 25 degrees C. These results strongly suggest that the self-emulsion system increased the stability of BCNU after released from PLGA wafer. From these results, it could be expected that the penetration depth of BCNU could be improved in brain tissue using self-emulsion system.

Antineoplastic Agents, Alkylating↗