Hillary A. Hahm

Apoptosis and Breast Cancer

Apoptosis is an integral part of normal mammary gland development, differentiation, and function. Numerous descriptive and mechanistic studies of programmed cell death pathways in normal and malignant mammary cells have been presented. This chapter reviews the evidence that established breast cancer treatments act via apoptotic pathways, and how ongoing laboratory work defining these pathways might lead to the development of new therapeutic ap proaches. Also, the possibility that evaluation of apoptotic-related molecules or events might serve as prognostic or predictive factors is discussed.

Novobiocin in Combination With High-Dose Chemotherapy for the Treatment of Advanced Breast Cancer: A Phase 2 Study

We conducted the first phase 2 and pharmacologic study to evaluate the combination of novobiocin (a coumeromycin antibiotic that has been shown to augment alkylating agent cytotoxicity in experimental models) and high-dose cyclophosphamide and thiotepa followed by autologous marrow support in women with chemosensitive advanced breast cancer. Its aims were (1) to determine progression-free survival (PFS) and overall survival (OS), (2) to evaluate the pharmacokinetics of cyclophosphamide and thiotepa, and (3) to measure the ability of novobiocin to reverse alkylator drug resistance in vitro. Forty-one women with chemotherapy-responsive advanced breast cancer received cyclophosphamide (4 g/m2) for peripheral blood stem cell mobilization (treatment 1) followed by high-dose cyclophosphamide (1.5 g/m2 per day for 4 days), thiotepa (200 mg/m2 per day for 4 days), and novobiocin (4 g/day orally for 7 days) (treatment 2) and autologous marrow support. The median PFS was 10 months (range, 0.2-70.6 months) and OS, 21.5 months (range, 0.2-70.6 months). There was no statistically significant relationship between PFS or OS and area-under-the-curve values of cyclophosphamide, thiotepa, or 4-hydroxycyclophosphamide. Patient plasma samples (n = 12) obtained during novobiocin therapy were able to reverse alkylator drug resistance in an in vitro colony-forming assay. Correlative laboratory studies in an in vitro model system demonstrated that patient plasma after novobiocin treatment resulted in the magnitude of resistance reversal that had been predicted by prior preclinical experiments. Clinically, however, this activity of novobiocin did not translate into a substantial increase in PFS or OS compared with historical controls treated with high-dose alkylator therapy alone.

Apoptosis in Hormone-Responsive Malignancies

Publisher Summary The breast and prostate cancer belong to the spectrum of hormone-related malignancies. So, this chapter seeks to review current knowledge about the role of programmed cell death in the normal development and function of the mammary and prostate glands, the carcinogenic process, and the prevention and therapy of breast and prostate cancers. Its suitability as a target for new therapies for both cancers is also explored. Although the focus of the chapter is on breast and prostate cancers, it seems likely that lessons learned from these two neoplasms is also of relevant to a variety of other epithelial malignancies. Breast and prostate represent two excellent model tissues in which to study the balance between cell proliferation and cell death in the normal setting. Research suggests that steroid hormones are key factors that promote proliferation and block death in both tissues. In addition, the pivotal role of programmed cell death in the normal lactational cycle of the breast has been identified. Furthermore, hormone-responsive breast and prostate cancers retain a similar programmed cell death pathway(s) that can be triggered by hormone withdrawal. Similar or identical pathways also exist in endocrine-unresponsive prostate and breast cancer cells even though hormonal manipulation is no longer capable of triggering these pathways. As the components of these pathways, their activators, and their inhibitors are delineated, these programmed cell death pathways provide opportunities for the development of new therapeutic approaches.