Topotecan, a novel chemotherapeutic agent that targets the DNA metabolizing enzyme topoisomerase I has shown activity in patients with relapsed, refractory leukemia, and myelodysplastic syndromes. The applicant's hypothesis is that improvements in remission rates in these patients are likely to require addition of effective cytotoxic agents given in combinations and schedules designed to modulate DNA repair mechanisms and overcome intrinsic drug resistance. In tumor cell lines topoisomerase I inhibitors are synergistic with cisplatin, in particular when administered sequentially, due to decreased repair of platinum associated DNA adducts. Concurrent administration of fludarabine and carboplatin has also been shown to enhance formation of platinum-DNA crosslinks. This application is a correlative laboratory investigation for a phase I protocol in which the applicant plans to administer daily fludarabine and continuous infusion carboplatin for 5 days followed by escalating doses of topotecan as a 72 hour infusion to patients with refractory/relapsed acute leukemia. Serial bone marrow aspirates obtained from patients during leukemia induction chemotherapy will be provide a unique opportunity to investigate pretreatment molecular characteristics and pharmacologic mechanisms of DNA repair in leukemic blasts. She anticipates that formation of DNA-associated platinum adducts will correlate with tumor response and that topotecan will reduce DNA-platinum adduct removal in a dose-dependent fashion. Specific laboratory studies will include 1) measuring formation of DNA-associated platinum adducts before and after topotecan and 2) correlating removal of DNA-associated platinum adducts with dose and serum level of topotecan and pretreatment topoisomerase I activity. These studies will provide a model for designing strategies to optimize safety and efficacy of treatment regimens for patients with acute leukemia.
| Cooper, Brenda W; Veal, Gareth J; Radivoyevitch, Tomas et al. (2004) A phase I and pharmacodynamic study of fludarabine, carboplatin, and topotecan in patients with relapsed, refractory, or high-risk acute leukemia. Clin Cancer Res 10:6830-9 |
