Modulation of High-Dose Alkylator Efficacy by Novobiocin

Kennedy, Michael

Abstract

The use of high-dose chemotherapy with autologous bone marrow support can produce remissions in large numbers of women with metastatic breast cancer, and a small proportion of these remissions appear to be durable. However the majority of patients relapse at sites of prior bulk disease. These results suggest that resistance to chemotherapy is a major impediment to improving the results of high-dose treatment. The mechanisms which enable tumor cells to survive exposure to cytotoxic agents are varied. Enhanced repair of damaged cellular DNA is one mechanism which may allow tumor cells to develop resistance to alkylating agents. The coumeramycin antibiotic novobiocin can potentiate the cytotoxic effects of a number of alkylating agents against cancer cell lines in-vitro by inhibiting DNA repair, perhaps through interaction with the cellular Topoisomerase II enzyme. In addition novobiocin may enhance cytotoxicity towards tumor cells to a greater extent than towards normal tissues and thus provide an increased therapeutic benefit. A Phase I clinical trial of novobiocin with conventional dose cyclophosphamide has provided evidence of acceptable toxicity and encouraging efficacy in patients with disease refractory to cyclophosphamide. The study proposed here will evaluate the toxicity, in-vitro efficacy, and mechanism of action of novobiocin in combination with high-dose cyclophosphamide and thiotepa for the treatment of metastatic breast cancer. Patients with metastatic breast will be treated with high-dose cyclophosphamide, thiotepa and novobiocin prior to marrow reinfusion. The dose of novobiocin will be escalated in sequential cohorts of patients. In each cohort the following parameters will be assessed; 1) toxicity; 2) novobiocin, cyclophosphamide and thiotepa levels and; 3) the ability of patient serum samples to augment alkylating agent cytotoxicity against a panel of human breast cancer cell lines in-vitro. Plasma novobiocin levels will be correlated with levels known to be necessary to, 1) augment cytotoxicity, 2) increase DNA crosslinking in a panel of human breast cancer cell lines and, 3) inhibit Topoisomerase II activity in a panel of human breast cancer cell lines. Thus this study will determine if a dose of novobiocin sufficient to augment alkylating agent cytotoxicity can be combined safely with high-dose alkylating agents and will evaluate the mechanism of action underlying this effect at each dose level.