The development of an intracerebral glioma model for brain tumor chemotherapy

Wassenaar, Willem; Tator, Charles H.; So, Wei Sum

doi:10.3171/jns.1973.39.3.0293

Cited by 17 publications

(9 citation statements)

References 4 publications

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“…The main attributes of the model are that it is simple, reproducible and produces a fully-vascularized malignant tumor that resembles glioblastoma multiforme from a completely avascular focus of neoplastic cells. In addition, it fulfills all the requirements of a good model as set forth by Wassenaar et al [3]; the tumor is of glial origin and grows intracerebrally, the blood supply is from the host brain parenchyma and not from extracerebral tissue, the cells infiltrate as well as grow as an expansive mass and the time required for tumor development is short.…”

Section: Discussionmentioning

confidence: 98%

“…Chemical, viral, and radiation induced tumors are less than ideal since they are of an unpredictable latency or produce a variety of tumor types [1]. The intracerebral injection technique is a satisfactory method for reproducible tumor production and has been used for a number of cell lines including C6 astrocytoma [2], ependymoma [3], 9L [4], RG [4], RG2.2 [5], $69-C15 [6] and RT9 [7]. However, the intracerebral inoculation of cells results in a diffuse intracranial tumor such that a well-demarcated interface between tumor and normal brain is uncommon [2].…”

Section: Introductionmentioning

confidence: 99%

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A new glioma model in rat: The C6 spheroid implantation technique permeability and vascular characterization

1987

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The C6 spheroid implantation glioma model is a simple, easily reproduced model for primary gliomas in which C6 astrocytoma cells are grown in vitro as spheroids and subsequently implanted into the brains of Sprague Dawley rat hosts. This report describes the growth, histology, vessel architecture and vascular permeability of the resulting tumors. The appearance of the tumor was investigated by light and electron microscopy, and by using the alkaline phosphatase technique. The leakage of tracer was measured from vessels in the tumor and peritumoral area at various times during tumor development. The spheroid implant produces a fully vascularized, rapidly growing tumor with many of the characteristics of glioblastoma multiforme, from an avascular focus of neoplastic cells. The major advantage of this model is that the tumors grow in a spheroidal fashion and the tumor-brain interface can be easily located. Many of the important events in the process of vascularization take place at the tumor-brain interface. Two distinctive vascular events appear to occur simultaneously: proliferation of blood vessels and their growth into the tumor mass so that they develop into typical, permeable tumor vessels, and migration of tumor cells along normal vessels into the surrounding brain. Tumor vessels were permeable to the tracer Evans Blue (EB) from the earliest days of ingrowth. Leakage of the EB increased as the tumors increased in size, but eventually leakage plateaued as tumors developed necrotic centers. It is well known that the structural and permeability characteristics of vessels associated with the tumor affect tumor growth. This model will be useful for a number of proposed studies including assessment of various clinical therapies on tumor growth and development, and more specifically, quantitative analysis of the vascularization process in tumors.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

A new glioma model in rat: The C6 spheroid implantation technique permeability and vascular characterization

1987

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“…37 Penicillin (50 units/ml) and streptomycin (50 rag/ ml) were added to the tumor cell suspension. A No.…”

Section: Tumor-cell Suspension and Tumor Implantationmentioning

confidence: 99%

The effect of phenobarbital on the toxicity and tumoricidal activity of CCNU in a murine brain tumor model

Müller¹,

Tator²,

Bloom³

1980

Journal of Neurosurgery

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v' The nitrosoureas are known to be substrates for hepatic microsomal enzymes. Since phenobarbital (PB) is a potent inducer of hepatic microsomal enzymes, and since PB and other enzyme-inducing drugs are commonly used in patients with brain tumors, the authors have assessed the effect of PB pretreatment on the toxic and tumoricidal activity of CCNU in a routine model.In C57B1/6J mice, PB pretreatment markedly reduced the lethal toxicity of high doses of CCNU. The LD,~ dose of CCNU was found to be 80 mg/kg given intraperitoneally. Pretreatment with PB reduced the toxic death rate of CCNU at 40, 60, 90, or 120 mg/kg to less than 10% (p < 0.01). Pretreatment with PB also reduced the tumoricidal activity of CCNU. In an intracerebral murine ependymoblastoma, intraperitoneal CCNU alone, at 30 mg/kg given on the 5th day after tumor transplantation, produced a percent increased life span (%ILS) of > 300, and 18 of 25 were long-term survivors (LTS). In contrast, after four daily doses of PB prior to the same dose of CCNU, the %ILS was reduced to 85 with no LTS among 25 mice (p < 0.01). When CCNU was given alone at 30 mg/kg intraperitoneally on Day 10, a %ILS of > 300 with 22 of 25 LTS resulted; whereas, PB pretreatment reduced the %ILS to 15, with two of 25 LTS (p < 0.01). When CCNU was administered directly into the tumors intracerebrally at 30 mg/kg on Day 10, the %ILS was > 300, with 16 of 20 LTS; whereas, PB pretreatment reduced the %ILS to 50 with five of 20 LTS (p < 0.01). Furthermore, PB pretreatment significantly reduced the ability of CCNU to retard tumor growth in a subcutaneous murine ependymoblastoma.Thus, PB pretreatment significantly altered the activity of CCNU. Since enzyme-inducing drugs are so commonly used in patients with brain tumors, it is possible that the clinical failure of nitrosoureas in some cases may be due to an unsuspected drug antagonism.

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“…The tumor was then trypsinized in Ca-Mg-free phosphatebuffered saline to produce a suspension of tumor cells containing 100,000 cells//~l as previously described. 49 After the addition of *The mice were obtained from the Jackson Laboratory, Bar Harbor, Maine.…”

Section: Tumor Cell Suspension and Intracerebral Implantationmentioning

confidence: 99%

Therapy of an experimental glioma with systemic or intraneoplastic methotrexate or radiation

Tator¹,

Wassenaar²,

Day³

et al. 1977

Journal of Neurosurgery

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An intracranial mouse glioma model was used to study the effectiveness of chemotherapy with methotrexate )MTX) or radiotherapy. Maximum tolerable doses of MTX were established by toxicity studies in nontumor-bearing mice for the intraperitoneal and intracerebral routes of drug administration with and without leucovorin as an antidote. These maximum tolerable doses were then given either by the intraperitoneal route or directly into the tumor to mice bearing intracerebral tumors. The glioma model proved to be extremely useful for assessing the modalities studied, including repeated intraneoplastic injection of MTX. Dosage schedules were successfully developed for administering large amount of MTX and for preventing systemic toxicity by the administration of the antidote. Radiotherapy in single doses and 800 rads delayed the median day of death and produced several long-term survivors. Higher doses were toxic. Intraperitoneal or intraneoplastic MTX was completely ineffective as a chemotherapeutic agent for this tumor, even though very large amounts could be delivered due to the protection from systemic toxicity afforded by leucovorin. It is concluded that MTX is a poor chemotherapeutic agent for this experimental brain tumor, but that the technique of intraneoplastic administration of chemotherapeutic agents is feasible with this model system and should be studied further.

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The development of an intracerebral glioma model for brain tumor chemotherapy

Cited by 17 publications

References 4 publications

A new glioma model in rat: The C6 spheroid implantation technique permeability and vascular characterization

A new glioma model in rat: The C6 spheroid implantation technique permeability and vascular characterization

The effect of phenobarbital on the toxicity and tumoricidal activity of CCNU in a murine brain tumor model

Therapy of an experimental glioma with systemic or intraneoplastic methotrexate or radiation

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