This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Clofarabine has been demonstrated in several Phase II studies to have significant activity in patients with relapsed or refractory acute myeloid leukemia, with a response rate as a single agent in the range of 30-40%. There is also evidence of a significant, synergistic interaction with ARA-C in vitro (the most important drug in the treatment of AML). Clofarabine appears to have more activity in patients with relapsed (as opposed to refractory) AML, and it is therefore anticipated that its activity will be greater in patients with de novo disease than those with relapsed disease. A Phase I/II study of Clofarabine with intermediate dose (as opposed to a standard lover dose, as will be given in CCF IRB 7253) ARA-C has shown the combination to be well tolerated and to have clinical activity in patients with relapsed disease. We therefore anticipate that, in addition to the single agent activity of Clofarabine, it will have a synergistic cytotoxic effect with ARA-C, and possibly overcome chemoresistance in patients with AML (i.e. Improve the complete remission rate). To investigate this effect, we will be monitoring the intra-cellular pharmacokinetics of Clofarabine and ARA-C together, to determine whether this synergistic effect occurs in vivo. We will aslo be evaluating the effects of ARA-C on the expression of apoptosis-related genes before and during therapy, to characterize blocks in the apoptosis signaling in AML cells, and to determine whether Clofarabine and ARA-C are able to overcome those blocks in apoptosis signaling. We will also determine the effects of Clofarabine and ARA-C on the quality of life patients in CCF IRB 7253 using standardized tools (questionnaires).
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