Improved treatment of a brain-tumor model

1983 ◽  
Vol 58 (3) ◽  
pp. 368-373 ◽  
Author(s):  
Massimo A. Gerosa ◽  
Dolores V. Dougherty ◽  
Charles B. Wilson ◽  
Mark L. Rosenblum
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Total Dose ◽  
Tumor Cells ◽  
Malignant Gliomas ◽  
Tumor Model ◽  
Content Type ◽  
Cell Kill ◽  
Brain Tumor Model ◽  
Anti Tumor Activity

✓ A combination chemotherapy regimen for brain tumors was developed, based on investigations of the survival of animals harboring the intracerebral 9L rat brain-tumor model and on analyses of their clonogenic tumor cells. Fischer 344 rats harboring 9L brain tumors were treated with 2-day courses of 5-fluorouracil (5-FU), in order to expose all cycling tumor cells to the drug during DNA synthesis and achieve maximum anti-tumor activity for this cell-cycle-specific anti-metabolite. Although a 74% cell kill was obtained for a total dose of 45 mg/kg or greater, animal life span was not increased over that of untreated tumor-bearing controls. However, when 5-FU (48 to 96 mg/kg total dose over 2 days) was administered after a single LD10 dose of BCNU (13.3 mg/kg), additive cell kill was suggested. In three large series, long-term animal survivors and occasional tumor cures were observed with this drug combination, a result never observed following BCNU alone. Schedule dependency was not apparent. A previously published protocol for treating recurrent malignant gliomas with sequential courses of BCNU and 5-FU was partially planned based upon these initial observations. Anti-tumor activity with the combination of drugs was superior to therapy with BCNU alone. Both animal and human studies confirm that, contrary to presently accepted oncological tenets, a chemotherapeutic agent that kills significant numbers of tumor cells but is clinically ineffective when given alone might, nevertheless, be useful in combination therapy regimens.

Establishment of a brain-tumor model in adult monkeys

1985 ◽  
Vol 63 (6) ◽  
pp. 912-916 ◽  
Author(s):  
Kazuo Tabuchi ◽  
Akira Nishimoto ◽  
Kengo Matsumoto ◽  
Toru Satoh ◽  
Susumu Nakasone ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Tumor Cells ◽  
Japanese Monkey ◽  
Protein A ◽  
Tumor Model ◽  
Chromosome Analysis ◽  
Content Type ◽  
Contrast Enhanced Ct ◽  
Brain Tumor Model

✓ A brain-tumor model in adult monkeys may be significant because of the biological similarity to humans as well as the feasibility for surgical manipulation and for sequential computerized tomography (CT) scanning. In the present study, brain tumors were successfully produced in Japanese monkeys (Macaca fuscata), each weighing 2 to 10.8 kg, with an average age of 5.1 years old. Tumor cells were implanted by intracerebral inoculation of 4 × 107 chick embryo fibroblasts infected with the Schmidt-Ruppin strain of Rous sarcoma virus (RSV). With a 15- to 67-day latency, brain tumors were induced in 11 (73.3%) of 15 RSV-inoculated monkeys. Contrast-enhanced CT scans delineated all solitary intracerebral tumors greater than 4 to 6 mm in diameter. The CT images were proved at autopsy to be accurate within 2 mm in determining the size of tumor. Five of the 11 monkeys with intracerebral tumors died, with an average survival time of 26.6 days after RSV inoculation. The induced tumors were classified as either glioma or sarcoma by the presence or absence of glial fibrillary acidic protein (GFAP) and S-100 protein. A chromosome analysis of cultured tumor cells showed a diploid number of 42, indicating monkey origin. It is concluded that the reproducible brain tumor in the adult Japanese monkey inoculated with RSV can serve as a good experimental brain-tumor model for the further study of human malignant brain tumors.

scholarly journals Vascular phenotyping of brain tumors using magnetic resonance microscopy (μMRI)

2011 ◽  
Vol 31 (7) ◽  
pp. 1623-1636 ◽  
Author(s):  
Eugene Kim ◽  
Jiangyang Zhang ◽  
Karen Hong ◽  
Nicole E Benoit ◽  
Arvind P Pathak
Keyword(s):  
Brain Tumor ◽  
Magnetic Resonance ◽  
Brain Tumors ◽  
Three Dimensional ◽  
Region Of Interest ◽  
Tumor Model ◽  
Magnetic Resonance Microscopy ◽  
Vascular Phenotype ◽  
Brain Tumor Model ◽  
Novel Method

Abnormal vascular phenotypes have been implicated in neuropathologies ranging from Alzheimer's disease to brain tumors. The development of transgenic mouse models of such diseases has created a crucial need for characterizing the murine neurovasculature. Although histologic techniques are excellent for imaging the microvasculature at submicron resolutions, they offer only limited coverage. It is also challenging to reconstruct the three-dimensional (3D) vasculature and other structures, such as white matter tracts, after tissue sectioning. Here, we describe a novel method for 3D whole-brain mapping of the murine vasculature using magnetic resonance microscopy (μMRI), and its application to a preclinical brain tumor model. The 3D vascular architecture was characterized by six morphologic parameters: vessel length, vessel radius, microvessel density, length per unit volume, fractional blood volume, and tortuosity. Region-of-interest analysis showed significant differences in the vascular phenotype between the tumor and the contralateral brain, as well as between postinoculation day 12 and day 17 tumors. These results unequivocally show the feasibility of using μMRI to characterize the vascular phenotype of brain tumors. Finally, we show that combining these vascular data with coregistered images acquired with diffusion-weighted MRI provides a new tool for investigating the relationship between angiogenesis and concomitant changes in the brain tumor microenvironment.

Effect of surgery on BCNU chemotherapy in a rat brain tumor model

1980 ◽  
Vol 52 (4) ◽  
pp. 529-532 ◽  
Author(s):  
Esref Tel ◽  
Takao Hoshino ◽  
Marvin Barker ◽  
Charles B. Wilson
Keyword(s):  
Cerebral Hemisphere ◽  
Tumor Model ◽  
Minimal Effect ◽  
Fischer 344 Rats ◽  
Tumor Patients ◽  
Content Type ◽  
Fischer 344 ◽  
Cell Kill ◽  
Rat Brain Tumor ◽  
Brain Tumor Model

✓ In Fischer 344 rats, 9L tumors were implanted in the left cerebral hemisphere. Compared with control animals not operated on, rats treated with an LD10 dose of BCNU 1 hour before or 1 or 12 hours after surgery on Day 16 postimplant had an increased life span of over 200% (greater than a 6 log cell kill). Minimal effect on survival was found when BCNU was administered during surgery. On the other hand, BCNU administered 12 hours before or 24 or 72 hours after surgery did not show any additive effect of surgery on BCNU treatment. These results suggest that in a clinical setting, a bolus of BCNU administered to tumor patients within 12 hours of surgery might increase substantially the total tumor cell kill compared with surgical resection alone.

scholarly journals Annexin A1-Binding Carbohydrate Mimetic Peptide Targets Drugs to Brain Tumors

2021 ◽  
Author(s):  
Michiko N. Fukuda ◽  
Misa Suzuki-Anekoji ◽  
Motohiro Nonaka
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
High Efficiency ◽  
Cytotoxic T Cells ◽  
Tumor Model ◽  
Tumor Vasculature ◽  
Cancer Drug ◽  
Annexin A1 ◽  
Mimetic Peptide ◽  
Brain Tumor Model

Annexin A1 (Anxa1) is expressed specifically on the surface of the tumor vasculature. Previously, we demonstrated that a carbohydrate-mimetic peptide, designated IF7, bound to the Anxa1 N-terminal domain. Moreover, intravenously injected IF7 targeted the tumor vasculature in mouse and crossed tumor endothelia cells to stroma via transcytosis. Thus, we hypothesized that IF7 could overcome the blood–brain barrier to reach brain tumors. Our studies in brain tumor model mice showed that IF7 conjugated with the anti-cancer drug SN38 suppressed brain tumor growth with high efficiency. Furthermore IF7-SN38-treated mice mounted an immune response to brain tumors established by injected tumor cells and shrank those tumors in part by recruiting cytotoxic T-cells to the injection site. These results suggest that Anxa1-binding peptide IF7 represents a drug delivery vehicle useful to treat malignant brain tumors. This chapter describes the unique development of IF7-SN38 as a potential breakthrough cancer chemotherapeutic.

The distribution of nuclear DNA from human brain-tumor cells

1978 ◽  
Vol 49 (1) ◽  
pp. 13-21 ◽  
Author(s):  
Takao Hoshino ◽  
Kazuhiro Nomura ◽  
Charles B. Wilson ◽  
Kathy D. Knebel ◽  
Joe W. Gray
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Human Brain ◽  
Dna Synthesis ◽  
Tumor Cells ◽  
Malignant Gliomas ◽  
Benign Tumors ◽  
Low Grade ◽  
Human Brain Tumor ◽  
Large Variability

✓ Flow cytometry (FCM) is a technique that measures the quantity of DNA contained in individual nuclei and records a frequency distribution of the DNA content per nucleus in the sampled cell population. Nuclei from a variety of human brain-tumor types were isolated by means of tissue grinding, purified by centrifugation through 40% sucrose (15 minutes at 4000 rpm), fixed with 10% formalin, stained with acriflavin-Feulgen, and analyzed by FCM. Profiles of DNA distribution in histologically benign tumors, such as meningiomas, pituitary adenomas, neuroblastomas, and low-grade astrocytomas, revealed a large diploid population (2C) with a few nuclei in DNA synthesis, as well as a small premitotic population (G2 cells) that contains a 4C DNA complement. In contrast, malignant gliomas, including glioblastomas, consist of more cells in DNA synthesis; these tumor cells show a highly variable distribution of ploidy consisting not only of diploid, and/or aneuploid, but also of triploid, tetraploid, and possibly octaploid populations. Also, a large variability between different regions of each tumor was always observed. In contrast, metastatic brain tumors, despite the fact that they contain a considerable number of cells undergoing DNA synthesis, demonstrate little variability within each individual tumor. The ability to rapidly characterize the cell populations of human brain tumors with FCM may enhance the effectiveness of their clinical management.

In vivo validation of tissue segmentation based on a 3D feature map using both a hamster brain tumor model and stereotactically guided biopsy of brain tumors in man

1998 ◽  
Vol 8 (4) ◽  
pp. 814-819 ◽  
Author(s):  
Simon Vinitski ◽  
Carlos Gonzalez ◽  
David Andrews ◽  
Robert Knobler ◽  
Mark Curtis ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Tumor Model ◽  
Tissue Segmentation ◽  
Feature Map ◽  
Guided Biopsy ◽  
Brain Tumor Model ◽  
In Vivo Validation

Improved treatment of a brain-tumor model

1983 ◽  
Vol 58 (2) ◽  
pp. 177-182 ◽  
Author(s):  
Mark L. Rosenblum ◽  
Massimo A. Gerosa ◽  
Dolores V. Dougherty ◽  
Charles B. Wilson
Keyword(s):  
Brain Tumor ◽  
Tumor Model ◽  
Clinical Effects ◽  
Content Type ◽  
Animal Survival ◽  
Fractionation Schedule ◽  
Brain Tumor Model ◽  
Clonogenic Cell ◽  
Survival Studies ◽  
Fine Print

✓ Clonogenic cell and animal survival studies were used to determine the most effective BCNU therapy schedule in the 9L rat brain-tumor model. Survival of tumor cells following a single LD10 dose of BCNU (13.3 mg/kg intraperitoneally) was compared to cell survival after one to four daily 0.5 × LD10 doses. The posttreatment kinetics of surviving clonogenic cells were investigated at various times after BCNU was given in single doses of 0.25 to 1 × LD10 and in two daily doses of 0.5 × LD10. The cell kill was greater, time to reinitiation of cell growth was later, posttreatment rate of clonogenic cell proliferation was slower, and the interval to total repopulation of the clonogenic cell pool was longer with a single LD10 dose as compared to the multiple-dose schedules. Animal survival studies confirmed that a single LD10 dose of BCNU was at least as effective as a cumulative level of up to 1½ times that amount when treatment was administered in smaller doses, regardless of the fractionation schedule. Clinical experience with patients harboring malignant brain tumors has shown that a single BCNU dose of 185 to 200 mg/sq m is tolerated well. Results of these animal experiments suggest that this therapy should have anti-tumor activity at least equivalent to the more commonly employed schedule of 80 mg/sq m/day given for 3 days. Although direct comparison of treatment efficacy using the two schedules is not possible, no adverse clinical effects have been observed with the recently adopted single-dose schedule. Furthermore, the duration of patient hospitalization for chemotherapy has decreased.

Doxorubicin encapsulated in sterically stabilized liposomes for the treatment of a brain tumor model: biodistribution and therapeutic efficacy

1995 ◽  
Vol 83 (6) ◽  
pp. 1029-1037 ◽  
Author(s):  
Tali Siegal ◽  
Aviva Horowitz ◽  
Alberto Gabizon
Keyword(s):  
Single Dose ◽  
Brain Tumor ◽  
Brain Tumors ◽  
Drug Exposure ◽  
Tumor Model ◽  
Drug Carriers ◽  
Tumor Inoculation ◽  
Drug Levels ◽  
Sterically Stabilized Liposomes ◽  
Brain Tumor Model

✓ Anthracyclines entrapped in small-sized, sterically stabilized liposomes have the advantage of long circulation time, reduced systemic toxicity, increased uptake into systemic tumors, and gradual release of their payload. To date, there is no information on the behavior of these liposomes in brain tumors. The objective of this study was to compare the biodistribution and clinical efficacy of free doxorubicin (F-DOX) and stealth liposome—encapsulated DOX (SL-DOX) in a secondary brain tumor model. Nine days after tumor inoculation Fischer rats with a right parietal malignant sarcoma received an intravenous dose of 6 mg/kg of either F-DOX or SL-DOX for evaluation of drug biodistribution. For therapeutic trials a single dose of 8 mg/kg was given 6 or 11 days after tumor induction, or alternatively, weekly doses (5 mg/kg) were given on Days 6,13, and 20. Liposome—encapsulated DOX was slowly cleared from plasma with a t1/2 of 35 hours. Free-DOX maximum tumor drug levels reached a mean value of 0.8 µg/g and were identical in the adjacent brain and contralateral hemisphere. In contrast, SL-DOX tumor levels were 14-fold higher at their peak levels at 48 hours, declining to ninefold increased levels at 120 hours. A gradual increase in drug levels in the brain adjacent to tumor was noted between 72 and 120 hours (up to 4 µg/g). High-performance liquid chromatography analysis identified a small amount of aglycone metabolites within the tumor mass from 96 hours and beyond, after SL-DOX injection. Cerebrospinal fluid levels were barely detectable in tumor-bearing rats treated with F-DOX up to 120 hours after drug injection (≥ 0.05 µg/ml), whereas the levels found after SL-DOX were 10- to 30-fold higher. An F-DOX single-dose treatment given 6 days after tumor inoculation increased the rats' life span (ILS) by 135% over controls (p < 0.05) but was not effective if given on Day 11. In contrast, SL-DOX treatment resulted in an ILS of 168% (p< 0.0003) with no difference when given after 6 or 11 days. Treatment with three weekly doses of SL-DOX produced an ILS of 189% compared to 126% by F-DOX (p < 0.0002). The authors conclude that the use of long-circulating liposomes as cytotoxic drug carriers in brain tumor results in enhanced drug exposure and improved therapeutic activity, with equal effectiveness against early small- and large-sized brain tumors.

scholarly journals CD9 Expression in Solid Non-neuroepithelial Tumors and Infiltrative Astrocytic Tumors

2002 ◽  
Vol 50 (9) ◽  
pp. 1195-1203 ◽  
Author(s):  
Masatou Kawashima ◽  
Katsumi Doh-ura ◽  
Eisuke Mekada ◽  
Masashi Fukui ◽  
Toru Iwaki
Keyword(s):  
Brain Tumor ◽  
Malignant Gliomas ◽  
Glioma Cells ◽  
Tumor Model ◽  
Surrounding Tissue ◽  
Low Grade ◽  
Astrocytic Tumors ◽  
Neuroepithelial Tumors ◽  
Brain Tumor Model ◽  
Murine Brain

The tetraspan membrane protein CD9 is normally expressed in the mature myelin sheath and is believed to suppress the metastatic potential of certain human tumors. In this study we identified CD9 in a variety of brain tumors by immunohistochemical (IHC) and immunoblotting analyses. We examined 96 tumor samples and three glioma cell lines in addition to a murine brain tumor model of transplanted glioma cells in CD9-deficient mice and control mice. CD9 was expressed not only in solid non-neuroepithelial tumors but also in infiltrative malignant neuroepithelial tumors. Among the neuroepithelial tumors, high-grade astrocytic tumors, including glioblastomas and anaplastic astrocytomas, showed higher immunoreactivity than low-grade cerebral astrocytomas. Thus, CD9 expression in astrocytic tumors correlated with their malignancy. In the murine brain tumor model, transplanted glioma cells were shown to grow and spread through myelinated areas irrespective of the presence or absence of CD9 expression in the recipient's brain. These results indicate that the CD9 expression of astrocytic tumors plays a significant role in the malignancy independent of CD9 expression in the surrounding tissue. This might be explained by the observation that the CD9 molecule is associated with a mitogenic factor, membrane-anchored heparin-binding epidermal growth factor, which is known to be upregulated in malignant gliomas.

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