Cyclophosphamide (CPA), an alkylating prodrug, has been used extensively in the treatment of hematologic malignancies, in particular, as an important component in the front-line regimens for non-Hodgkin lymphoma and chronic lymphocytic leukemia. Unfortunately, despite aggressive chemotherapy, a significant number of patients remain uncured due to development of drug resistance and/or intolerable toxicities. The need for further optimization of the current regimens is evident. The overall goal of this proposal is to improve the therapeutic efficacy of CPA-based chemotherapy by enhancing metabolic conversion of CPA to the pharmacologically active 4-hydroxylcyclophosphamide (4-OH-CPA) via CYP2B6, but not to the N- dechloroethyl-cyclophosphamide and the toxic chloroacetaldehyde by CYP3A4. Towards this end, we have shown that activation of the human constitutive androstane receptor (hCAR) preferentially induced the expression of hepatic CYP2B6 over CYP3A4 and increased the formation of 4-OH-CPA. We have also developed a unique human primary hepatocyte (HPH)-leukemia coculture model and demonstrated that co- administration of CPA with a selective hCAR activator leads to significantly enhanced apoptosis in leukemia cells without increasing hepatotoxicity. In this application, we hypothesize that activation of hCAR can selectively enhance systemic exposure to 4-OH-CPA and increase the efficacy:toxicity ratio of CPA-based treatment for lymphoma and leukemia. This central hypothesis will be tested by the following specific aims:
Aim #1. Evaluate the role of hCAR in the bioactivation of CPA in HPH and lymphoma/leukemia cells;
Aim #2. Assess the metabolism and anticancer activity of CPA in the HPH-lymphoma/leukemia coculture model;
and Aim #3. Examine the influence of hCAR activation on CPA-based treatment of lymphoma/leukemia in an hCAR-transgenic mouse model. The outcomes are expected to establish hCAR as a novel therapeutic target facilitating the CPA-based chemotherapy for hematopoietic malignancies. Improved understanding of the underlying mechanism(s) associated with hCAR-mediated enhancement of the anticancer activity of CPA may ultimately benefit the development of new therapeutic strategies.
We will evaluate the role of hCAR in the metabolism and anticancer activity of CPA using our newly developed human hepatocyte-leukemia coculture model in vitro and a hCAR-transgenic mouse model in vivo. We expect that results from the proposed research will fundamentally advance our understanding of the molecular modulation of CPA bioactivation, and will eventually benefit the development of novel therapeutic strategies.
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|Yang, Hui; Garzel, Brandy; Heyward, Scott et al. (2014) Metformin represses drug-induced expression of CYP2B6 by modulating the constitutive androstane receptor signaling. Mol Pharmacol 85:249-60|