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Busulfan therapy of central nervous system xenografts in athymic mice
R H Aaron1, G B Elion, O M Colvin
1Department of Pediatrics, Duke University Medical Center, Durham, NC 27710.
Abstract:
We evaluated the antitumor activity of busulfan against a panel of tumor cell lines and xenografts in athymic nude mice derived from childhood high-grade glioma, adult high-grade glioma, ependymoma, and medulloblastoma. Busulfan displayed similar activity against a panel of four medulloblastoma cell lines (D283 Med, Daoy, D341 Med, and D425 Med) and four corresponding sublines with laboratory-generated or clinically acquired resistance to 4-hydroperoxycyclophosphamide [D283 Med (4-HCR), Daoy (4-HCR), D341 Med (4-HCR), and D458 Med] and cross-resistance to melphalan. This is consistent with a nearly total lack of cross-resistance of busulfan to 4-hydroperoxycyclophosphamide. Busulfan was active in the therapy of all but one of the subcutaneous xenografts tested, with growth delays ranging from 14.3 days in D612 EP to 58.4 days in D528 EP. Busulfan produced statistically significant increases in the median survival of mice bearing intracranial D456 MG (66%-90%), D612 EP (18%-33%), and D528 EP (89%) xenografts. These studies suggest that busulfan may be active against medulloblastomas, high-grade gliomas, and ependymomas as well as against cyclophosphamide-resistant neoplasms.
Insights
Busulfan shows significant antitumor activity against pediatric and adult brain tumors, including medulloblastoma, high-grade glioma, and ependymoma. It is effective even against tumors resistant to other chemotherapy drugs like cyclophosphamide.
Area of Science:
- Oncology
- Pharmacology
- Pediatric Oncology
Background:
- Childhood brain tumors like medulloblastoma and high-grade glioma are challenging to treat.
- Developing effective therapies, especially for drug-resistant cancers, remains a critical need.
Purpose of the Study:
- To evaluate the antitumor activity of busulfan against various pediatric and adult brain tumor models.
- To assess busulfan's efficacy in both cell line and xenograft models, including those with acquired drug resistance.
Main Methods:
- Testing busulfan's activity against medulloblastoma, high-grade glioma, and ependymoma cell lines.
- Evaluating busulfan's therapeutic effect on subcutaneous and intracranial xenografts in athymic nude mice.
- Assessing cross-resistance patterns with cyclophosphamide and melphalan.
Main Results:
- Busulfan demonstrated consistent activity against medulloblastoma cell lines, including those resistant to 4-hydroperoxycyclophosphamide.
- Significant tumor growth delays were observed in subcutaneous xenografts treated with busulfan.
- Busulfan significantly increased median survival in mice with intracranial xenografts of medulloblastoma, high-grade glioma, and ependymoma.
Conclusions:
- Busulfan exhibits promising antitumor activity against a range of brain tumors, including medulloblastomas, high-grade gliomas, and ependymomas.
- The drug's effectiveness against cyclophosphamide-resistant neoplasms suggests potential for overcoming treatment resistance.
- Busulfan warrants further investigation as a therapeutic agent for these challenging pediatric and adult brain cancers.