Myeloprotection by Cytidine Deaminase Gene Transfer in Antileukemic Therapy

Abstract

Gene transfer of drug resistance (CTX-R) genes can be used to protect the hematopoietic system from the toxicity of anticancer chemotherapy and this concept recently has been proven by overexpression of a mutant O(6)-methylguaninemethyltransferase in the hematopoietic system of glioblastoma patients treated with temozolomide. Given its protection capacity against such relevant drugs as cytosine arabinoside (ara-C), gemcitabine, decitabine, or azacytidine and the highly hematopoiesis-specific toxicity profile of several of these agents, cytidine deaminase (CDD) represents another interesting candidate CTX-R gene and our group recently has established the myeloprotective capacity of CDD gene transfer in a number of murine transplant studies. Clinically, CDD overexpression appears particularly suited to optimize treatment strategies for acute leukemias and myelodysplasias given the efficacy of ara-C (and to a lesser degree decitabine and azacytidine) in these disease entities. This article will review the current state of the art with regard to CDD gene transfer and point out potential scenarios for a clinical application of this strategy. In addition, risks and potential side effects associated with this approach as well as strategies to overcome these problems will be highlighted.

Efficiency and Safety of O6-Methylguanine DNA Methyltransferase (MGMTP140K)-MediatedIn VivoSelection in a Humanized Mouse Model

“…This applies specifically to myeloprotective gene therapy approaches employing the (over)expression of selectable drug-resistant genes in hematopoietic stem and progenitor cells (Lachmann et al, 2013), as here the exposure to cytotoxic and mutagenic agents and the proliferative stress exerted during the in vivo selection process associated with this approach represent additional genotoxic risk factors. Besides mutants of the dehydrofolate reductase enzyme or the multidrug resistance 1 (MDR1) gene, mutants of the O 6 -methylguanine DNA methyltransferase (MGMT) gene have been investigated with considerable success in this context.…”

Zebularine-Resistant Human Cytidine Deaminase Mutants for Optimal Chemoprotection of Hematopoietic Stem Cells

“…Drug resistance may be mediated by several factors, including low transporter levels and low deoxycytidine kinase (dCK) activity [1]. Furthermore, high human cytidine deaminase (hCDA) activity has been suggested to play an important role not only in drug resistance but also to protect cells from drug-mediated cytotoxicity (myeloprotection) [1,2]. Human CDA is an evolutionarily conserved enzyme involved in the pyrimidine salvage pathway and catalyzes the deamination of cytidine and deoxycytidine to uridine and deoxyuridine, respectively.…”

“…This could explain why some cytidine analogs have greater antitumor efficacy in vitro but limited effects in vivo, especially in liver cancer cells. Further evidence that high hCDA activity negatively impacts therapeutic outcome was found in leukemic cells, especially in those from patients who have relapsed after Ara-C therapy [1,2]. Mahfouz et al [4] also found that increased hCDA expression contributes to decreased cytidine analog half-life and likely also to poor outcomes following cytidine analog therapy.…”

“…Overexpression of drug resistance genes in HSCs has become a promising approach to overcome this hematologic toxicity. Several chemotherapy drug resistance genes such as human O 6 -methylguanine-DNA-methyltransferase, multidrug resistance 1 (MDR-1) and hCDA have demonstrated myeloprotective potential in vitro and in vivo [2,7,8]. Human CDA represents the most relevant drug inactivating gene for myeloprotection in the context of acute leukemia or myelodysplasia therapy.…”

Optimization of cytarabine (ARA-C) therapy for acute myeloid leukemia

“…Cells that overexpress CR deaminase show signs of drug resistance to ARA-C [24,25]. We detected an increased expression of CR deaminase in leukemic blasts after treatment with decitabine [19].…”