Abstract
There is no effective therapy for breast cancer that has spread to the brain. A major roadblock is the blood-brain barrier (BBB), which prevents the usual breast cancer drugs from effectively reaching intracranial metastases. The alkylating agent temozolomide (TMZ) is able to penetrate the BBB and has become the gold standard for chemotherapeutic treatment of glioblastoma. However, when it was tested in clinical trials for activity against brain metastases of breast cancer, the results were mixed and ranged from "encouraging activity" to "no objective responses." In an effort to generate an agent with greater activity against intracranial breast metastases, we synthesized a TMZ analog where the natural product perillyl alcohol (POH) was covalently linked to TMZ's amide functionality. The resulting novel compound, called TMZ-POH (T-P), displayed greatly increased anticancer activity in a variety of breast cancer cell lines, inclusive of TMZ-resistant ones. It caused DNA damage and cell death much more efficiently than its parental compound TMZ, because linkage with POH increased its biologic half-life and thus provided greater opportunity for placement of cytotoxic DNA lesions. In an intracranial mouse tumor model with triple-negative breast cancer, T-P revealed considerably greater therapeutic efficacy than TMZ, where a single cycle of treatment extended median survival benefit from 6 days (in the case of TMZ) to 28 days. At the same time, T-P seemed to be well tolerated by the animals. Thus, T-P may have potential as a novel therapy for brain-targeted breast cancer metastases.
Highlights
There is no effective therapy for breast cancer that has spread to the brain
Previous studies showed that perillyl alcohol (POH) is able to exert cytotoxic effects in cancer cells, concentrations approaching the millimolar range were required [34, 35]
MDA-MB-231 cells were treated with the individual compounds (T-P, TMZ, or POH) alone, or with an equimolar mix of TMZ plus POH, and cell survival was analyzed by colony formation assay (CFA)
Summary
There is no effective therapy for breast cancer that has spread to the brain. This therapeutic challenge once was a late aspect of disease progression, but increasingly is becoming a first site of disease progression after otherwise successful treatment of primary tumor and metastases outside the cranium [1]. Current therapeutic approaches consist of surgery, radiation, and chemotherapy. Chemotherapy is obstructed by the inability of most chemotherapeutic agents to effectively penetrate the blood–brain barrier (BBB). Traditional breast cancer therapeutics, such as paclitaxel or doxorubicin, only reach brain metastases at concentrations that are far lower than needed to be therapeutically active [2]. Authors' Affiliations: Departments of 1Neurosurgery, 2Pathology, 3Molecular Microbiology and Immunology, and 4Pharmaceutical Sciences, University of Southern California, Los Angeles, California
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