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The critical role of angiogenesis in the growth of solid tumors, including neoplasms of the central nervous system, has provided the impetus for research leading to the discovery of inhibitors of tumor neovascularization. The therapeutic potential of systemically administered antiangiogenic drugs for brain tumors, however, is limited by a variety of anatomic and physiologic barriers to drug delivery. Implantable controlled-release polymers for local drug administration directly into the tumor parenchyma have therefore been developed to achieve therapeutic concen-trations of these drugs within the brain while minimizing systemic toxicity. With use of these polymers, successfull antiangiogenic therapy for treatment of experimental intracranial malignancies has been achieved. This has been demonstrated with a variety of otherwise unrelated drugs – including the angiostatic steroids, tetracycline derivatives, and amiloride – which modulate collagenase activity, and thus, basement membrane and interstitial matrix metabolism. Controlled‐release polymers provide a clinically practicable method of achieving sustained antian-giogenic therapy which can be readily used in combination with other treatment modalities such as cytoreductive surgery, radiation, and cytotoxic chemotherapy.

A young patient surviving four years after treatment for primary intracerebral small-cell osteosarcoma is reported. This 16-year-old girl presented with headaches, visual disturbance, and papilledema and was found to have a large, heavily calcified mass in the left parietal lobe. A gross total resection of the tumor was performed and pathologic analysis revealed a small-cell osteosarcoma. Thoracic computerized tomography (CT) scans and a complete bone scan showed no other lesions. The patient received adjuvant chemotherapy and radiotherapy. She continues to do well with no evidence of metastases or local recurrence 4 years after her initial presentation. The clinical, radiographic, surgical, pathologic, and immunohistochemical features of this case, along with therapeutic interventions and outcome, are presented.

Therapy of brain tumors has been limited by lack of effective methods of drug delivery. Systemic administration often fails to achieve therapeutic concentrations of drugs within intracranial tumors despite toxic systemic levels. This article discusses new methods for delivering therapeutic agents to brain tumors, including intra-arterial, intrathecal, intraventricular, and interstitial administration techniques.

✓ This study was designed to explore the question of whether minocycline, a semisynthetic tetracycline shown to inhibit tumor-induced angiogenesis, could control the growth of the rat intracranial 9L gliosarcoma. Minocycline was tested alone and in combination with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in vivo. Treatment was started at the time of intracranial implantation of 9L gliosarcoma into male Fischer 344 rats, 5 days later, or after tumor resection. Minocycline was delivered locally with a controlled-release polymer or systemically by intraperitoneal injection. Systemic minocycline did not extend survival time. Local treatment with minocycline by a controlled-release polymer implanted at the time of tumor implantation extended median survival time by 530% (p < 0.001) compared to treatment with empty polymer. When treatment was begun 5 days after tumor implantation, minocycline delivered locally or systemically had no effect on survival. However, after tumor resection, treatment with locally delivered minocycline resulted in a 43% increase in median survival time (p < 0.002) compared to treatment with empty polymer. Treatment with a combination of minocycline delivered locally in a controlled-release polymer and systemic BCNU 5 days after tumor implantation resulted in a 93% extension of median survival time compared to BCNU alone (p < 0.002). In contrast, treatment with a combination of systemic minocycline and BCNU did not increase survival time compared to systemic BCNU alone. These results demonstrate that minocycline affects tumor growth when delivered locally and suggest that minocycline may be a clinically effective modulator of intracranial tumor growth when used in combination with a chemotherapeutic agent and surgical resection.

OBJECTIVE: L-buthionine sulfoximine (BSO) inhibits glutathione synthesis and may modulate tumor resistance to some alkylating agents, but it has not been proven effective in the treatment of intracranial neoplasms. To evaluate this drug for the treatment of brain tumors, we studied the use of BSO for potentiating the antineoplastic effect of 4-hydroxyperoxycyclophosphamide (4-HC) in the rat 9L glioma model. METHODS: The survival of male Fischer 344 rats with intracranial 9L gliomas was measured after implantation of controlled-release polymers containing one of the following: no drug, BSO, 4-HC, or both BSO and 4-HC. The efficacy of intracranial 4-HC treatment was assessed with and without serial systemic intraperitoneal BSO injections. Tissue glutathione levels were measured in the brains, tumors, and livers of animals treated with intraperitoneal injections or local delivery of BSO. RESULTS: The median survival of animals treated with intracranial polymers containing 4-HC was 2.3 times greater than that of controls. This survival benefit was doubled by local delivery of BSO. In contrast, systemic BSO therapy did not improve survival time. In animals that were treated systemically, both liver and tumor glutathione levels were significantly lower than they were in control animals. In the locally treated animals, glutathione levels were reduced in the brain tumor but not in the liver. CONCLUSION: These results demonstrate that local but not systemic delivery of BSO enhances the antineoplastic effect of 4-HC in this rat 9L glioma model. In addition, because local delivery of BSO within the brain did not deplete glutathione levels systemically, this method of treatment may be safer than systemic administration of BSO.