Itraconazole Effect on Oxymetholone Disposition

Georgetown University, Washington DC

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Abstract

The treatment of advanced or recurrent squamous cell carcinoma of the cervix has been improved in recent years by the introduction of new active cytotoxic agents such as cisplatin, the control of advanced or recurrent disease is problematic and in most cases temporary. The use of combination chemotherapy has been demonstrated to improve response rates in patients with advanced disease, however overall median survival was not impacted upon. The lack of success with conventional chemotherapeutic agents relates to several factors. First a significant proportion of patients have recurrences in the pelvis at the site of prior radiotherapy and delivery of drug to the cancer can be impaired by altered blood supply. Second patients who have previously received pelvic radiotherapy have limited bone marrow reserves and are less tolerant of intensive chemotherapy and doses of cytotoxic drugs are often less than optimal. Finally recurrent or advanced cervix cancer may be associated with ureteral obstruction and resultant renal failure, complicating the use of renally excreted agents and eliminating the use of potentially nephrotoxic ones. Bryostatin-1 (NSC 339555) has both antitumor and immunomodulatory activity. A proposed mechanism for its effects is through modulation of protein kinase C (PKC). Based on the anti-tumor activity observed in patients with gynecologic malignancies in phase I studies, the tolerable side-effect profile of bryostatin, preclinical evidence of synergy with classical anti-neoplastic agents, and its novel mechanism of action, a logical next step in development of this agent is to assess its efficacy in patients with relapsed cervical cancer. Therefore in the present study we propose to compare the efficacy and toxicity of bryostatin administered over either 1 or 72 hours in this patient population. In addition the role of schedule of administration on the pharmacology and immunomodulatory effects of bryostatin will be assessed using a bioassay and fluorescence activated cell sorting.